Collagen peptide-based medicament compositions and devices and methods of production and use thereof

ABSTRACT

The present invention is in the fields of medicinal chemistry, biotechnology and pharmaceuticals. The invention provides compositions comprising one or more collagen mimetic peptides, optionally attached to one or more therapeutic compounds or one or more imaging compounds, for use in methods of treating, preventing, ameliorating, curing and diagnosing certain diseases and physical disorders in humans and veterinary animals, as well as methods of manufacturing such composition. The invention also provides medical devices comprising one or more such compositions of the invention. The invention also provides methods of use of such compositions and devices in treating and diagnosing certain diseases and physical disorders in humans and veterinary animals, including ocular diseases or disorders, skin diseases or disorders, certain cancers, particularly intraluminal cancers, gastrointestinal diseases or disorders, genitourinary tract diseases or disorders, fibrotic diseases/disorders and rheumatic diseases/disorders.

CROSS-REFERENCE TO RELATED APPLICATIONS AND INCORPORATION BY REFERENCE

The present application is a continuation of U.S. patent applicationSer. No. 17/820,400, filed Aug. 17, 2022, which is a continuation ofU.S. patent application Ser. No. 17/749,729, filed May 20, 2022, whichis a continuation of U.S. patent application Ser. No. 16/839,987, filedApr. 3, 2020, which is a continuation of U.S. patent application Ser.No. 15/945,820, filed Apr. 5, 2018, which claims the benefit of U.S.Provisional Patent Application Nos. 62/482,592, filed on Apr. 6, 2017,and 62/581,927, filed Nov. 6, 2017, both entitled “Collagen-BasedMedicament Compositions and Devices and Methods of Production and UseThereof” and naming as inventors Eric Schlumpf, Robert Baratta and ShawnA. DeLorey. The contents of each of these applications are incorporatedherein by reference in their entireties.

STATEMENT REGARDING FEDERALLY-SPONSORED RESEARCH AND DEVELOPMENT

Not applicable.

NAMES OF THE PARTIES TO A JOINT RESEARCH AGREEMENT

Not applicable.

REFERENCE TO SEQUENCE LISTING SUBMITTED ELECTRONICALLY

The contents of the electronic sequence listing (0123-0001US5_SL.xml;Size: 1548 KB; and Date of Creation Aug. 12, 2022) submitted herewith,is herein incorporated by reference in its entirety.

STATEMENT REGARDING PRIOR DISCLOSURES BY THE INVENTOR OR A JOINTINVENTOR

Some of the material disclosed herein was disclosed and claimed in U.S.Provisional Patent Application Nos. 62/482,592, filed Apr. 6, 2017, and62/581,927, filed Nov. 6, 2017, both entitled “Collagen-Based MedicamentCompositions and Devices and Methods of Production and Use Thereof”, andnaming as inventors Richard Eric Schlumpf, Robert Baratta and Shawn A.DeLorey.

BACKGROUND OF THE INVENTION Field of the Invention

The present invention is in the fields of medicinal chemistry,biotechnology, pharmaceuticals and medical devices, as well as the useof medicinal compounds and medical devices for the treatment, preventionand amelioration of diseases, disorders and physical ailments in humansand veterinary animals.

Background Art

Collagen is the most abundant protein in vertebrates, and is thefundamental structural protein for vertebrate tissues, occurring invirtually every tissue including skin and other epithelial tissues(including the lining of most luminal organs such as those of thegastrointestinal tract), tendons, bone, blood vessels, cartilage,ligaments and teeth. In humans, collagen makes up about a third of thetotal protein and about three-quarters of the dry weight of skin (seeShoulders, M. D., and Raines, R. T., Ann. Rev. Biochem. 78:929-958(2009); Gelse, K., et al., Adv. Drug Deliv. Rev. 55:1531-1546 (2003)).

Collagen is a fibrous protein that is composed of a triple helix, whichgenerally consists of two identical chains and a third chain thatdiffers slightly in its chemical composition. Mammals produce at least46 distinct collagen polypeptide chains that combine to form variants or“types” of collagen. To date, 28 types of collagen have been described.Collagen types are generally grouped according to their structuralforms: fibrillar (types I, II, III, V and XI) which represent about 90%of all collagen protein found in mammals, and non-fibrillar (basementmembrane or type IV, and other non-fibrillar collagen types withinterrupted helix structures) see Id.). The five most common types ofcollagen, and their tissue distributions, are:

-   -   Type I: skin, tendon, organs, bone, vascular connective tissue;    -   Type II: cartilage;    -   Type III: reticular connective tissue, often associated with        Type I collagen;    -   Type IV: basement membranes of epithelial tissues and certain        solid tumors; and    -   Type V: hair, placenta, external cellular membranes.

In each of these variants, the polypeptide chains of collagen arecomposed of approximately 300 repeats of the amino acids proline (Pro),4(R)-hydroxyproline (Hyp) and glycine (Gly), usually in the sequenceX-Y-Gly, where X is often a Pro residue and Y is often a (Hyp) residue;in vertebrates, the typical repeat motif in collagen is ProProGly (seeHulmes, D. J. S., “Collagen Diversity, Synthesis and Assembly,” in:Collagen: Structure and Mechanics, P. Fratzl, Ed., New York: Springer,pp. 15-47 (2008)). Subsequently, in vivo, the hydroxylation of Proresidues is performed enzymatically after collagen biosynthesis butbefore the chains begin to form a triple helix. Thus, hydroxylation ofat least one Pro residue in the ProProGly motif, typically formingProHypGly, appears to be important for both the proper folding andstability of the collagen triple helix, both of which are key to thenormal structure and function of collagen in vivo (see Shoulders, M. D.,and Raines, R. T., Ann. Rev. Biochem. 78:929-958 (2009)). For example,the melting temperature of a triple helix of (ProHypGly)₁₀ (SEQ ID NO:396) chains is 58° C., while that of a triple helix of (ProProGly)10(SEQ ID NO: 397) chains is only 24° C. (Sakakibara et al., Biochim.Biophys. Acta, 303:198-202 (1973)), and the rate at which (ProHypGly)₁₀(SEQ ID NO: 397) chains fold into a triple helix is substantiallygreater than the corresponding rate for (ProProGly)₁₀ (SEQ ID NO: 397)chains (Chopra and Ananthanarayanan, Proc. Natl. Acad. Sci. USA,79:7180-7184 (1982)).

Type I collagen is the most abundant and best-studied collagen. Inhumans and most other animals it forms more than 90% of the organic massof bone and is the major collagen of tendons, skin, ligaments, cornea,and many interstitial connective tissues with the exception of a veryfew such as hyaline cartilage, brain and the vitreous body. The collagentype I triple helix is usually formed as a heterotrimer by two identicalal chains and one α2 chain. The triple helical fibers are, in vivo,primarily incorporated into composite fibrils containing other types ofcollagens, which as noted above vary depending upon tissue type andlocation (Fleischmajer, E. D. et al., J. Struct. Biol. 105: 162-169(1990); Niyibizi, C. and Eyre, D. R., Connect. Tissue Res. 20: 247-250(1989)). In most organs and notably in tendons and fascia, type Icollagen provides tensile rigidity and in bone, it defines thebiomechanical properties relating to load bearing, tensile strength andtorsional stiffness.

In connective tissues (such as bone, tendon, cartilage, ligament, skin,blood vessels and teeth), individual collagen molecules are woundtogether in tight triple helices. These helices are organized intofibrils of great tensile strength (Jones & Miller, J. Mol. Biol.,218:209-219 (1991)) via cross-linking of individual triple helix fibers(Lodish, H. et al., “Collagen: The Fibrous Proteins of the Matrix”, in:Molecular Cell Biology, 4th ed., Section 22.3, New York: W. H. Freeman(2000)). Varying the arrangements and cross linking of the collagenfibrils enables vertebrates to support stress in one dimension(tendons), two dimensions (skin) or three dimensions (cartilage).

Collagens serve within the body to a considerable extent for themaintenance of the structural integrity of tissues and organs. In allparenchymal organs, collagens represent the major component of theinterstitial matrix as well as the basement membranes, while in allconnective tissues, particularly bone and cartilage, collagens providethe major functional backbone of the structures. Besides thebiomechanical aspects, however, collagens are also involved in a varietyof additional functions. For example, specific cell surface andintracellular receptors interact with collagens, and signaling by thesereceptors is involved in cellular adhesion, differentiation, growth andother cellular activities, as well as the survival of cells both in vivoand in vitro (Vogel, W. F., Eur. J. Dermatol. 11: 506-514 (2001); Gelse,K., et al., Adv. Drug Deliv. Rev. 55:1531-1546 (2003)). Collagens alsoare involved in the entrapment, local storage and delivery of growthfactors and cytokines in a variety of tissues in which the collagens arefound. Through these receptor interactions and storage and deliveryfunctions, collagen plays a key role in organ development, wound healingand tissue repair (Chattopadhyay, S. and R. Raines, Biopolymers 101:821-833 (2014); Yamaguchi, Y. et al., Nature 346: 281-284 (1990); Hay,E. D., J. Cell Biol. 91:205s-223s (1981); Bautista, C. M. et al.,Metabolism 39: 96-100 (1990); Zhu, Y. et al., J. Cell Biol. 144:1069-1080 (1998); Schlegel, K. A. et al., Biomaterials 25:5387-5393(2004); Kumar, V. A., et al., Biomacromol. 15: 1484-1490 (2014)). Thesefunctions also qualify collagens as candidate transport vehicles for thedelivery of therapeutic compounds (see, e.g., Chattopadhyay, S. et al.,J. Tissue Eng. Regen. Med. 10:1012-1020 (2012); Schuppan, D. et al.,Gastroenterol. 114: 139-152 (1998); Frenkel, S. R. et al., J. Bone Jt.Surg. 79-B: 831-836 (1997); Albu, M. G. et al., “Collagen-Based DrugDelivery Systems for Tissue Engineering”, in: Biomaterials Applicationsfor Nanomedicine, Pignatello, R. (Ed.), ISBN: 978-953-307-661-4, DOI:10.5772/22981, Rijeka, Croatia: InTech, available from:intechopen.com/books/biomaterials-applications-for-nanomedicine/collagen-based-drug-delivery-systems-for-tissue-engineering(2011)), and for use in wound healing by directly promoting tissuerepair or regeneration (Wakitani, S. et al., J. Bone Jt. Surg. 71-B:74-80 (1989); Kumar, V. A., et al., Biomacromol. 15: 1484-1490 (2014)).Collagen (more particularly, disrupted collagen) has also beenimplicated in tumor progression and metastasis in humans and othervertebrates (for a review of this issue, see Fang, M., et al., TumorBiol. 35:2871-2882 (2014)).

Beyond intact collagen molecules, however, fragments of collagen mayalso have potential therapeutic uses, and indeed, may perform in asuperior fashion relative to native collagen. For example,non-collagenous fragments of collagens IV, XV and XVIII have been shownto promote the growth of blood vessels and tumor cells, and to influencea variety of other cellular activities (Ortega, N. and Werb, Z., J. CellSci. 115: 4201-4214 (2002); Davis, G. E. et al., Am. J. Pathol. 156:1489-1498 (2000); O'Reilly, M. S. et al., Cell 88: 277-285 (1997)).Analogously, as described in greater detail below, fragments orsynthetic collagen mimetic peptides (CMPs) of collagen type I haverecently been studied for their utility in treatment of diseases andmedical disorders, both as active pharmaceutical ingredients (APIs) intheir own right and in the delivery of a skin wound-healing agent (seeU.S. Pat. Nos. 5,973,112, 7,122,521, 7,858,741, and U.S. Patent Publ.No. US 2007/0275897 A1, the disclosures of all of which are incorporatedherein by reference in their entireties; see also e.g., Chattopadhyay,S. et al., J. Tissue Eng. Regen. Med. 10:1012-1020 (2012); Kumar, V. A.et al., Biomacromolecules 15:1484-1490 (2014)).

Collagen abnormalities are associated with a wide variety of humandiseases, including diseases and disorders of the eye such as cataractsand glaucoma (Coudrillier, B., et al., PLoS ONE 10: e0131396 (2015);Huang, W. et al., Med. Sci. Monit. Basic Res. 19: 237-240 (2013); Dua,H. S., et al., Br. J. Ophthalmol. 98: 691-697 (2014)), arthritis,rheumatism, brittle bones, atherosclerosis and cirrhosis. Disruptions incollagen are also associated with certain human and veterinary diseasessuch as certain cancers (particularly carcinomas of the luminal organs,and certain sarcomas); see, e.g., Lauer, J. L., and Fields, G. B.,“Collagen in Cancer”, in The Tumor Microenvironment, New York: Springer,pp. 477-507 (2010). Collagen is also critically important in woundhealing and is known to be upregulated in areas of epithelial woundswhere healing is taking place (see, e.g., U.S. Pat. Nos. 5,973,112 and7,122,521, which are incorporated herein by reference in theirentireties; see also Chattopadhyay, S., et al., J. Tissue Eng. Regen.Med. 10:1012-1020 (2012); Chattopadhyay, S., et al., Org. Biomol. Chem.10:5892-5897 (2012); Kumar, V. A., et al., Biomacromol. 15: 1484-1490(2014)), including in the skin and the cornea of the eye. Indeed,collagen, collagen fragments or certain mimetic peptides of naturalcollagen have been reported to show promise in treating certain woundsand diseases in humans and animals, particularly skin wounds (see, e.g.,U.S. Pat. Nos. 5,973,112, 7,122,521, 7,858,741, and U.S. Patent Publ.No. US 2007/0275897 A1, all of which are incorporated herein byreference in their entireties; see also Kumar, V. A. et al.,Biomacromolecules 15:1484-1490 (2014)). It is thought that thesecollagen fragments or collagen mimetic peptides may specifically targetareas of collagen disruption associated with skin wounds byintercalating into the disrupted collagen and reforming the nativecollagen I triple helix (see, e.g., Chattopadhyay, S., et al., J. TissueEng. Regen. Med. 10:1012-1020 (2012); Chattopadhyay, S., et al., Org.Biomol. Chem. 10:5892-5897 (2012)). As a result, there have beenattempts made to use collagen as a vehicle for delivering certain drugs,with varying degrees of success (see, e.g., B. An, et al., Adv. DrugDeliv. Rev. 97:69-84 (2016); V. Chak, et al., Intl. J. Pharm. Teachingand Practices 4:811 (2013)). Collagen mimetic peptides have also beenused in a topical application to deliver a conjugated therapeuticcompound, the neuropeptide known as Substance P, to areas of skinwounds; such CMP-Substance P conjugates have been shown to acceleratewound healing in a mouse skin model (Chattopadhyay, S., et al., J.Tissue Eng. Regen. Med. 10:1012-1020 (2012)).

Treatments for diseases/disorders are expensive, difficult to deliverwith specificity, and may have deleterious effects at sites distal tothe intended site of action. For example, many medicinal compositions,including antibiotics, small molecule therapeutics (e.g., anti-cancercompounds) and biologics (e.g., monoclonal antibody therapeutics) areadministered parenterally in a non-targeted fashion and must diffuse orotherwise find their way to the site of the affliction before they areable to provide their therapeutic benefits. This “shotgun approach” totherapy necessarily requires higher dosing and can result in longerperiods of therapy and reduced patient compliance than a therapeuticapproach which would deliver therapeutic compounds and compositions in amore targeted fashion which would allow for controlled or programmablerelease at or near the site of the affliction in a human or veterinaryanimal.

Thus, there is a need in the art for drug delivery systems—i.e.,compositions and methods of use—that will overcome many of theseshortcomings in traditional treatments for certain diseases anddisorders in humans and veterinary animals. Such advanced drug deliverysystems would allow the use of lower doses of medication and moretargeted delivery of the medications to the intended sites of action, aswell as reducing the therapeutic problems or delays resulting frompatient non-compliance. There also is a need for medical devices coatedwith such compositions which will facilitate more rapid healing andrecovery in humans and animals suffering from such diseases anddisorders. Finally, there is a need in the art for methods of producingsuch compositions and medical devices that will meet the needs of themedical and patient communities in maximizing treatment efficacies whilereducing costs.

BRIEF SUMMARY OF THE INVENTION

The present inventors reasoned that since collagen disruption isassociated with a variety of diseases and disorders in humans and otheranimals, the conjugation of a variety of therapeutic compounds and/ordiagnostic compounds to collagen or collagen mimetic peptides wouldprovide an elegant, rapid and reproducible way of overcoming many of theabove-referenced limitations in drug delivery. Thus, the presentinvention provides such drug delivery systems, medical devices andmethods of manufacturing the same. Accordingly, the present inventionmeets the needs in the art as expressed hereinabove.

In one aspect, the invention provides compositions comprising one ormore collagen mimetic peptides (CMPs), which in certain embodiments havebeen conjugated one or more therapeutic compounds and/or one or morediagnostic compounds thereby forming CMP conjugates and compositions.Such CMPs and CMP conjugates, and compositions comprising such CMPsand/or CMP conjugates, are useful in treating, preventing, amelioratingand diagnosing a variety of diseases, disorders and physical conditionsin humans and veterinary animals. In certain embodiments of this aspect,the invention provides compositions comprising such CMPs and/or CMPconjugates and one or more pharmaceutically acceptable carriers,excipients or compounding agents, and optionally one or more additionaltherapeutic or diagnostic agents, to provide therapeutic and diagnosticcompositions useful in treating, preventing, ameliorating or diagnosingcertain diseases and disorders in humans and veterinary animals.

In another aspect, the invention provides methods of treating,preventing, ameliorating or diagnosing certain diseases and disorders inhumans and veterinary animals, by administering the conjugates and/orcompositions of the invention to a human or veterinary animal sufferingfrom or predisposed to such diseases or disorders. Diseases anddisorders suitably treated, prevented, cured, ameliorated or diagnosesaccording to this aspect of the invention include ocular diseases ordisorders, skin diseases or disorders, cancers, gastrointestinaldiseases or disorders, genitourinary tract diseases or disorders,fibrotic diseases or disorders, cardiovascular diseases or disorders,bone diseases or disorders, and rheumatic diseases or disorders.

In yet another aspect, the invention provides medical devices coatedwith or comprising one or more of the conjugates or compositions of theinvention. In related aspects, the invention provides methods oftreating, curing, preventing or ameliorating diseases or disorders inhumans or veterinary animals comprising implanting one or more of themedical devices of this aspect of the invention into the human orveterinary animal, under conditions such that the disease or disorder istreated, cured, prevented or ameliorated.

In still other aspects, the invention provides methods of manufacturingthe compositions, conjugates and medical devices of the invention.

Other objects, advantages, and features of the present invention will bereadily apparent to those of ordinary skill in the art upon review ofthe description, drawings, examples and claims presented herein.

BRIEF DESCRIPTION OF THE DRAWING

The FIG. 1 s a series of photomicrographs depicting the healing of awound in the cornea of mouse eye, at time 0 and 16 hours post-wounding,upon treatment with certain compositions of the present invention.Wounds were introduced into the corneas of mice, and the mice treatedimmediately after wounding with vehicle (PBS), with 100 ng/mL ofepidermal growth factor (EGF), or with 25 nM (about 3 mg/kg) of a(Pro-Pro-Gly)₇ CMP of the invention (SEQ ID NO:1) (“Cmpd 3”), or of a(Hyp-Pro-Gly)₇-SubP CMP-TC of the invention (SEQ ID NO:390) (“Cmpd 10”).The extent of the remaining corneal abrasion and damage to theunderlying corneal stroma was then revealed with fluorescein stainingand fluorescence photomicrography of the eyes at time 0 and 16 hourspost-wounding.

DETAILED DESCRIPTION OF THE INVENTION

Unless defined otherwise, all technical and scientific terms used hereinhave the same meanings as commonly understood by one of ordinary skillin the arts to which this invention belongs. Although any methods andmaterials similar or equivalent to those described herein can be used inthe practice or testing of the present invention, the preferred methodsand materials are described hereinafter.

According to a first aspect, the invention provides compositionssuitable for use in a medicament for treating or preventing a disease ordisorder in a human or veterinary animal in need of treatment orprevention of such a disease or disorder. In certain embodiments, thecompositions provided by the invention comprise (a) at least onecollagen mimetic peptide (CMP) attached to at least one therapeuticcompound (TC) to form a CMP-TC conjugate, and (b) one or morepharmaceutically suitable carriers.

In certain embodiments of the invention, the collagen mimetic peptidecomprises, consists essentially of or consists of an amino acid sequencethat is a multimeric repeat of a specific tripeptide having a sequence(Xaa-Yaa-Gly)_(n), (SEQ ID NO: 398) wherein Xaa is independentlyselected from the group consisting of proline, 4S-hydroxyproline,fluoroproline, chloroproline, lysine, cysteine and methionine; whereinYaa is independently selected from the group consisting of proline,4R-hydroxyproline, fluoroproline, chloroproline, lysine, cysteine andmethionine; wherein Gly is a glycine residue; and wherein n is aninteger ranging from 1 to 20, such as from 3 to 15, from 5 to 15, orfrom 5 to 10, and is preferably 5, 6, 7, 8, 9 or 10.

In certain embodiments of the invention, the collagen mimetic peptidecomprises, consists essentially of or consists of an amino acid sequencethat is or corresponds to a 21-mer comprising seven repeats of a threeamino acid sequence of proline-proline-glycine ((Pro-Pro-Gly)₇), i.e.,an amino acid sequence of:Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly(SEQ ID NO:1).

In certain other embodiments of the invention, the collagen mimeticpeptide comprises, consists essentially of or consists of an amino acidsequence that is or corresponds to a 21-mer comprising seven repeats ofa three amino acid sequence in which hydroxyproline (Hyp), andpreferably a 4S-hydroxyproline residue, has been substituted forproline₁ in SEQ ID NO:1, yielding a sequence of seven repeats of4S-hydroxyproline-proline-glycine ((Hyp-Pro-Gly)₇), i.e., an amino acidsequence of:Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly(SEQ ID NO:2).

In certain other embodiments of the invention, the collagen mimeticpeptide comprises, consists essentially of or consists of an amino acidsequence that is or corresponds to a 21-mer comprising seven repeats ofa three amino acid sequence in which Hyp, and preferably a4S-hydroxyproline residue, has been substituted for proline₂ in SEQ IDNO:1, yielding a sequence of seven repeats of4S-hydroxyproline-proline-glycine ((Pro-Hyp-Gly)₇), i.e., an amino acidsequence of:Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly(SEQ ID NO:3).

In certain other embodiments of the invention, the collagen mimeticpeptide comprises, consists essentially of or consists of an amino acidsequence that is or corresponds to a 21-mer comprising seven repeats ofa three amino acid sequence in which fluoroproline (Flp) has beensubstituted for proline₁ in SEQ ID NO:1, yielding a sequence of sevenrepeats of fluoroproline-proline-glycine ((Flp-Pro-Gly)₇), i.e., anamino acid sequence of:Flp-Pro-Gly-Flp-Pro-Gly-Flp-Pro-Gly-Flp-Pro-Gly-Flp-Pro-Gly-Flp-Pro-Gly-Flp-Pro-Flp-Gly(SEQ ID NO:4).

In certain other embodiments of the invention, the collagen mimeticpeptide comprises, consists essentially of or consists of an amino acidsequence that is or corresponds to a 21-mer comprising seven repeats ofa three amino acid sequence in which Flp has been substituted forproline₂ in SEQ ID NO:1, yielding a sequence of seven repeats ofproline-fluoroproline-glycine ((Pro-Flp-Gly)₇), i.e., an amino acidsequence of:Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly(SEQ ID NO:5).

In certain other embodiments of the invention, the collagen mimeticpeptide comprises, consists essentially of or consists of an amino acidsequence that is or corresponds to a 21-mer comprising seven repeats ofa three amino acid sequence in which fluoroproline (Flp) has beensubstituted for proline₁ in SEQ ID NO:1 and Hyp has been substituted forproline₂ in SEQ ID NO:1, yielding a sequence of seven repeats offluoroproline-hydroxyproline-glycine ((Flp-Hyp-Gly)₇), i.e., an aminoacid sequence of:Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly(SEQ ID NO:6).

In CMPs containing Flp, the Flp moiety may be in the 4-cis or 4-transconfiguration, and preferably is in the 4-cis configuration.

In certain other embodiments of the invention, the collagen mimeticpeptide may comprise, consist of or have an amino acid sequence that isor corresponds to a 21-mer comprising seven repeats of a three aminoacid sequence in which chloroproline (Clp) has been substituted forproline₁ in SEQ ID NO:1, yielding a sequence of seven repeats ofchloroproline-proline-glycine ((Clp-Pro-Gly)₇), i.e., an amino acidsequence of:Clp-Pro-Gly-Clp-Pro-Gly-Clp-Pro-Gly-Clp-Pro-Gly-Clp-Pro-Gly-Clp-Pro-Gly-Clp-Pro-Gly(SEQ ID NO:7).

In certain other embodiments of the invention, the collagen mimeticpeptide may comprise, consist of or have an amino acid sequence that isor corresponds to a 21-mer comprising seven repeats of a three aminoacid sequence in which chloroproline (Clp) has been substituted forproline₂ in SEQ ID NO:1, yielding a sequence of seven repeats ofproline-chloroproline-glycine ((Pro-Clp-Gly)₇), i.e., an amino acidsequence of:Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly(SEQ ID NO:8).

In certain other embodiments of the invention, the collagen mimeticpeptide comprises, consists essentially of or consists of an amino acidsequence that is or corresponds to a 21-mer comprising seven repeats ofa three amino acid sequence in which Clp has been substituted forproline₁ in SEQ ID NO:1 and Hyp has been substituted for proline₂ in SEQID NO:1, yielding a sequence of seven repeats ofchloroproline-hydroxyproline-glycine ((Clp-Hyp-Gly)₇), i.e., an aminoacid sequence of:Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Clp-Gly(SEQ ID NO:9).

In CMPs containing Clp, the Clp moiety may be in the 4-cis or 4-transconfiguration, and preferably is in the 4-cis configuration.

In certain other embodiments of the invention, the collagen mimeticpeptide may comprise, consist of or have an amino acid sequence that isor corresponds to a 21-mer of any one of SEQ ID NOs:1-9, in which atleast one cysteine (Cys) residue has been substituted for at least oneof the proline residues in SEQ ID NO:1, at least one of thehydroxyproline residues in SEQ ID NOs:2-3 and 6, at least one of thefluoroproline residues in SEQ ID NOs:4-6, or at least one of thechloroproline residues in SEQ ID NOs:7-9, yielding, for example, thefollowing sequences:

(SEQ ID NO: 10) Pro-Pro-Gly-Pro-Pro-Gly-Cys-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro- Gly; (SEQ ID NO: 11)Hyp-Pro-Gly-Hyp-Pro-Gly-Cys-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro- Gly; (SEQ ID NO: 12)Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Cys-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp- Gly; (SEQ ID NO: 13)Pro-Flp-Gly-Pro-Flp-Gly-Pro-Cys-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp- Gly; (SEQ ID NO: 14)Pro-Clp-Gly-Pro-Clp-Gly-Pro-Cys-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp- Gly; (SEQ ID NO: 15)Cys-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro- Gly; (SEQ ID NO: 16)Pro-Cys-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro- Gly; (SEQ ID NO: 17)Pro-Pro-Gly-Cys-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro- Gly; (SEQ ID NO: 18)Pro-Pro-Gly-Pro-Cys-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro- Gly; (SEQ ID NO: 19)Pro-Pro-Gly-Pro-Pro-Gly-Pro-Cys-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro- Gly; (SEQ ID NO: 20)Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Cys-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro- Gly; (SEQ ID NO: 21)Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Cys-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro- Gly; (SEQ ID NO: 22)Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Cys-Pro-Gly-Pro-Pro-Gly-Pro-Pro- Gly; (SEQ ID NO: 23)Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Cys-Gly-Pro-Pro-Gly-Pro-Pro- Gly; (SEQ ID NO: 24)Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Cys-Pro-Gly-Pro-Pro- Gly; (SEQ ID NO: 25)Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Cys-Gly-Cys-Pro- Gly; (SEQ ID NO: 26)Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Cys-Pro- Gly; (SEQ ID NO: 27)Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Cys- Gly; (SEQ ID NO: 28)Cys-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro- Gly; (SEQ ID NO: 29)Hyp-Cys-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro- Gly; (SEQ ID NO: 30)Hyp-Pro-Gly-Cys-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro- Gly; (SEQ ID NO: 31)Hyp-Pro-Gly-Hyp-Cys-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro- Gly; (SEQ ID NO: 32)Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Cys-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro- Gly; (SEQ ID NO: 33)Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Cys-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro- Gly; (SEQ ID NO: 34)Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Cys-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro- Gly; (SEQ ID NO: 35)Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Cys-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro- Gly; (SEQ ID NO: 36)Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Cys-Gly-Hyp-Pro-Gly-Hyp-Pro- Gly; (SEQ ID NO: 37)Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Cys-Pro-Gly-Hyp-Pro- Gly; (SEQ ID NO: 38)Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Cys-Gly-Hyp-Pro- Gly; (SEQ ID NO: 39)Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Cys-Pro- Gly; (SEQ ID NO: 40)Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Cys- Gly; (SEQ ID NO: 41)Cys-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp- Gly; (SEQ ID NO: 42)Pro-Cys-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp- Gly; (SEQ ID NO: 43)Pro-Hyp-Gly-Cys-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp- Gly; (SEQ ID NO: 44)Pro-Hyp-Gly-Pro-Cys-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp- Gly; (SEQ ID NO: 45)Pro-Hyp-Gly-Pro-Hyp-Gly-Cys-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp- Gly; (SEQ ID NO: 46)Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Cys-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp- Gly; (SEQ ID NO: 47)Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Cys-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp- Gly; (SEQ ID NO: 48)Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Cys-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp- Gly; (SEQ ID NO: 49)Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Cys-Gly-Pro-Hyp-Gly-Pro-Hyp- Gly; (SEQ ID NO: 50)Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Cys-Hyp-Gly-Pro-Hyp- Gly; (SEQ ID NO: 51)Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Cys-Gly-Pro-Hyp- Gly; (SEQ ID NO: 52)Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Cys-Hyp- Gly; (SEQ ID NO: 53)Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Cys- Gly; (SEQ ID NO: 54)Cys-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp- Gly; (SEQ ID NO: 55)Pro-Cys-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp- Gly; (SEQ ID NO: 56)Pro-Flp-Gly-Cys-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp- Gly; (SEQ ID NO: 57)Pro-Flp-Gly-Pro-Cys-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp- Gly; (SEQ ID NO: 58)Pro-Flp-Gly-Pro-Flp-Gly-Cys-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp- Gly; (SEQ ID NO: 59)Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Cys-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp- Gly; (SEQ ID NO: 60)Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Cys-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp- Gly; (SEQ ID NO: 61)Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Cys-Flp-Gly-Pro-Flp-Gly-Pro-Flp- Gly; (SEQ ID NO: 62)Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Cys-Gly-Pro-Flp-Gly-Pro-Flp- Gly; (SEQ ID NO: 63)Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Cys-Flp-Gly-Pro-Flp- Gly; (SEQ ID NO: 64)Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Cys-Gly-Pro-Flp- Gly; (SEQ ID NO: 65)Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Cys-Flp- Gly; (SEQ ID NO: 66)Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Cys- Gly; (SEQ ID NO: 67)Cys-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp- Gly; (SEQ ID NO: 68)Pro-Cys-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp- Gly; (SEQ ID NO: 69)Pro-Flp-Gly-Cys-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp- Gly; (SEQ ID NO: 70)Pro-Flp-Gly-Pro-Cys-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp- Gly; (SEQ ID NO: 71)Pro-Flp-Gly-Pro-Flp-Gly-Cys-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp- Gly; (SEQ ID NO: 72)Pro-Flp-Gly-Pro-Flp-Gly-Pro-Cys-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp- Gly; (SEQ ID NO: 73)Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Cys-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp- Gly; (SEQ ID NO: 74)Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Cys-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp- Gly; (SEQ ID NO: 75)Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Cys-Flp-Gly-Pro-Flp-Gly-Pro-Flp- Gly; (SEQ ID NO: 76)Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Cys-Gly-Pro-Flp-Gly-Pro-Flp- Gly; (SEQ ID NO: 77)Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Cys-Flp-Gly-Pro-Flp- Gly; (SEQ ID NO: 78)Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Cys-Gly-Pro-Flp- Gly; (SEQ ID NO: 79)Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Cys-Flp- Gly; (SEQ ID NO: 80)Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Cys- Gly; (SEQ ID NO: 81)Cys-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp- Gly; (SEQ ID NO: 82)Flp-Cys-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp- Gly; (SEQ ID NO: 83)Flp-Hyp-Gly-Cys-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp- Gly; (SEQ ID NO: 84)Flp-Hyp-Gly-Flp-Cys-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp- Gly; (SEQ ID NO: 85)Flp-Hyp-Gly-Flp-Hyp-Gly-Cys-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp- Gly; (SEQ ID NO: 86)Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Cys-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp- Gly; (SEQ ID NO: 87)Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Cys-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp- Gly; (SEQ ID NO: 88)Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Cys-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp- Gly; (SEQ ID NO: 89)Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Cys-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp- Gly; (SEQ ID NO: 90)Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Cys-Gly-Flp-Hyp-Gly-Flp-Hyp- Gly; (SEQ ID NO: 91)Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Cys-Hyp-Gly-Flp-Hyp- Gly; (SEQ ID NO: 92)Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Cys-Gly-Flp-Hyp- Gly; (SEQ ID NO: 93)Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Cys-Hyp- Gly; (SEQ ID NO: 94)Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Cys- Gly; (SEQ ID NO: 95)Cys-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp- Gly; (SEQ ID NO: 96)Pro-Cys-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp- Gly; (SEQ ID NO: 97)Pro-Clp-Gly-Cys-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp- Gly; (SEQ ID NO: 98)Pro-Clp-Gly-Pro-Cys-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp- Gly; (SEQ ID NO: 99)Pro-Clp-Gly-Pro-Clp-Gly-Cys-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp- Gly; (SEQ ID NO: 100)Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Cys-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp- Gly; (SEQ ID NO: 101)Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Cys-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp- Gly; (SEQ ID NO: 102)Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Cys-Clp-Gly-Pro-Clp-Gly-Pro-Clp- Gly; (SEQ ID NO: 103)Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Cys-Gly-Pro-Clp-Gly-Pro-Clp- Gly; (SEQ ID NO: 104)Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Cys-Clp-Gly-Pro-Clp- Gly; (SEQ ID NO: 105)Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Cys-Gly-Pro-Clp- Gly; (SEQ ID NO: 106)Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Cys-Clp- Gly; (SEQ ID NO: 107)Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Cys- Gly; (SEQ ID NO: 108)Cys-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp- Gly; (SEQ ID NO: 109)Pro-Cys-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp- Gly; (SEQ ID NO: 110)Pro-Clp-Gly-Cys-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp- Gly; (SEQ ID NO: 111)Pro-Clp-Gly-Pro-Cys-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp- Gly; (SEQ ID NO: 112)Pro-Clp-Gly-Pro-Clp-Gly-Cys-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp- Gly; (SEQ ID NO: 113)Pro-Clp-Gly-Pro-Clp-Gly-Pro-Cys-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp- Gly; (SEQ ID NO: 114)Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Cys-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp- Gly; (SEQ ID NO: 115)Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Cys-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp- Gly; (SEQ ID NO: 116)Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Cys-Clp-Gly-Pro-Clp-Gly-Pro-Clp- Gly; (SEQ ID NO: 117)Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Cys-Gly-Pro-Clp-Gly-Pro-Clp- Gly; (SEQ ID NO: 118)Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Cys-Clp-Gly-Pro-Clp- Gly; (SEQ ID NO: 119)Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Cys-Gly-Pro-Clp- Gly; (SEQ ID NO: 120)Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Cys-Clp- Gly; (SEQ ID NO: 121)Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Cys- Gly; (SEQ ID NO: 122)Cys-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp- Gly; (SEQ ID NO: 123)Clp-Cys-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp- Gly; (SEQ ID NO: 124)Clp-Hyp-Gly-Cys-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp- Gly; (SEQ ID NO: 125)Clp-Hyp-Gly-Clp-Cys-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp- Gly; (SEQ ID NO: 126)Clp-Hyp-Gly-Clp-Hyp-Gly-Cys-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp- Gly; (SEQ ID NO: 127)Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Cys-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp- Gly; (SEQ ID NO: 128)Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Cys-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp- Gly; (SEQ ID NO: 129)Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Cys-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp- Gly; (SEQ ID NO: 130)Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Cys-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp- Gly; (SEQ ID NO: 131)Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Cys-Gly-Clp-Hyp-Gly-Clp-Hyp- Gly; (SEQ ID NO: 132)Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Cys-Hyp-Gly-Clp-Hyp- Gly; (SEQ ID NO: 133)Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Cys-Gly-Clp-Hyp- Gly; (SEQ ID NO: 134)Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Cys-Hyp- Gly; and (SEQ ID NO: 135)Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Cys- Gly.

In certain other embodiments of the invention, the collagen mimeticpeptide may comprise, consist of or have an amino acid sequence that isor corresponds to a 21-mer of any one of SEQ ID NOs: 1-9, in which atleast one methionine (Met) residue has been substituted for at least oneof the proline residues in SEQ ID NO:1, at least one of thehydroxyproline residues in SEQ ID NOs:2-3 and 6, at least one of thefluoroproline residues in SEQ ID NOs:4-6, or at least one of thechloroproline residues in SEQ ID NOs:7-9, yielding, for example, thefollowing sequences:

(SEQ ID NO: 136)Pro-Pro-Gly-Pro-Pro-Gly-Met-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly; (SEQ ID NO: 137)Hyp-Pro-Gly-Hyp-Pro-Gly-Met-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly; (SEQ ID NO: 138)Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Met-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly; (SEQ ID NO: 139)Pro-Flp-Gly-Pro-Flp-Gly-Pro-Met-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly; (SEQ ID NO: 140)Pro-Clp-Gly-Pro-Clp-Gly-Pro-Met-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly; (SEQ ID NO: 141)Met-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly; (SEQ ID NO: 142)Pro-Met-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly; (SEQ ID NO: 143)Pro-Pro-Gly-Met-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly; (SEQ ID NO: 144)Pro-Pro-Gly-Pro-Met-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly; (SEQ ID NO: 145)Pro-Pro-Gly-Pro-Pro-Gly-Pro-Met-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly; (SEQ ID NO: 146)Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Met-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly; (SEQ ID NO: 147)Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Met-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly; (SEQ ID NO: 148)Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Met-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly; (SEQ ID NO: 149)Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Met-Gly-Pro-Pro-Gly-Pro-Pro-Gly; (SEQ ID NO: 150)Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Met-Pro-Gly-Pro-Pro-Gly; (SEQ ID NO: 151)Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Met-Gly-Pro-Pro-Gly; (SEQ ID NO: 152)Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Met-Pro-Gly; (SEQ ID NO: 153)Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Met-Gly; (SEQ ID NO: 154)Met-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly; (SEQ ID NO: 155)Hyp-Met-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly; (SEQ ID NO: 156)Hyp-Pro-Gly-Met-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly; (SEQ ID NO: 157)Hyp-Pro-Gly-Hyp-Met-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly; (SEQ ID NO: 158)Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Met-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly; (SEQ ID NO: 159)Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Met-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly; (SEQ ID NO: 160)Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Met-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly; (SEQ ID NO: 161)Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Met-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly; (SEQ ID NO: 162)Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Met-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly; (SEQ ID NO: 163)Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Met-Pro-Gly-Hyp-Pro-Gly; (SEQ ID NO: 164)Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Met-Gly-Hyp-Pro-Gly; (SEQ ID NO: 165)Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Met-Pro-Gly; (SEQ ID NO: 166)Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Met-Gly; (SEQ ID NO: 167)Met-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly; (SEQ ID NO: 168)Pro-Met-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly; (SEQ ID NO: 169)Pro-Hyp-Gly-Met-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly; (SEQ ID NO: 170)Pro-Hyp-Gly-Pro-Met-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly; (SEQ ID NO: 171)Pro-Hyp-Gly-Pro-Hyp-Gly-Met-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly; (SEQ ID NO: 172)Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Met-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly; (SEQ ID NO: 173)Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Met-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly; (SEQ ID NO: 174)Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Met-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly; (SEQ ID NO: 175)Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Met-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly; (SEQ ID NO: 176)Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Met-Hyp-Gly-Pro-Hyp-Gly; (SEQ ID NO: 177)Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Met-Gly-Pro-Hyp-Gly; (SEQ ID NO: 178)Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Met-Hyp-Gly; (SEQ ID NO: 179)Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Met-Gly; (SEQ ID NO: 180)Met-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly; (SEQ ID NO: 181)Pro-Met-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly; (SEQ ID NO: 182)Pro-Flp-Gly-Met-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly; (SEQ ID NO: 183)Pro-Flp-Gly-Pro-Met-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly; (SEQ ID NO: 184)Pro-Flp-Gly-Pro-Flp-Gly-Met-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly; (SEQ ID NO: 185)Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Met-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly; (SEQ ID NO: 186)Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Met-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly; (SEQ ID NO: 187)Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Met-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly; (SEQ ID NO: 188)Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Met-Gly-Pro-Flp-Gly-Pro-Flp-Gly; (SEQ ID NO: 189)Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Met-Flp-Gly-Pro-Flp-Gly; (SEQ ID NO: 190)Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Met-Gly-Pro-Flp-Gly; (SEQ ID NO: 191)Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Met-Flp-Gly; (SEQ ID NO: 192)Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Met-Gly; (SEQ ID NO: 193)Met-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly; (SEQ ID NO: 194)Pro-Met-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly; (SEQ ID NO: 195)Pro-Flp-Gly-Met-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly; (SEQ ID NO: 196)Pro-Flp-Gly-Pro-Met-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly; (SEQ ID NO: 197)Pro-Flp-Gly-Pro-Flp-Gly-Met-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly; (SEQ ID NO: 198)Pro-Flp-Gly-Pro-Flp-Gly-Pro-Met-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly; (SEQ ID NO: 199)Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Met-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly; (SEQ ID NO: 200)Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Met-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly; (SEQ ID NO: 201)Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Met-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly; (SEQ ID NO: 202)Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Met-Gly-Pro-Flp-Gly-Pro-Flp-Gly; (SEQ ID NO: 203)Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Met-Flp-Gly-Pro-Flp-Gly; (SEQ ID NO: 204)Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Met-Gly-Pro-Flp-Gly; (SEQ ID NO: 205)Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Met-Flp-Gly; (SEQ ID NO: 206)Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Met-Gly; (SEQ ID NO: 207)Met-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly; (SEQ ID NO: 208)Flp-Met-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly; (SEQ ID NO: 209)Flp-Hyp-Gly-Met-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly; (SEQ ID NO: 210)Flp-Hyp-Gly-Flp-Met-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly; (SEQ ID NO: 211)Flp-Hyp-Gly-Flp-Hyp-Gly-Met-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly; (SEQ ID NO: 212)Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Met-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly; (SEQ ID NO: 213)Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Met-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly; (SEQ ID NO: 214)Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Met-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly; (SEQ ID NO: 215)Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Met-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly; (SEQ ID NO: 216)Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Met-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly; (SEQ ID NO: 217)Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Met-Hyp-Gly-Flp-Hyp-Gly; (SEQ ID NO: 218)Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Met-Gly-Flp-Hyp-Gly; (SEQ ID NO: 219)Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Met-Hyp-Gly; (SEQ ID NO: 220)Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Met-Gly; (SEQ ID NO: 221)Met-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly; (SEQ ID NO: 222)Pro-Met-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly; (SEQ ID NO: 223)Pro-Clp-Gly-Met-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly; (SEQ ID NO: 224)Pro-Clp-Gly-Pro-Met-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly; (SEQ ID NO: 225)Pro-Clp-Gly-Pro-Clp-Gly-Met-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly; (SEQ ID NO: 226)Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Met-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly; (SEQ ID NO: 227)Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Met-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly; (SEQ ID NO: 228)Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Met-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly; (SEQ ID NO: 229)Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Met-Gly-Pro-Clp-Gly-Pro-Clp-Gly; (SEQ ID NO: 230)Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Met-Clp-Gly-Pro-Clp-Gly; (SEQ ID NO: 231)Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Met-Gly-Pro-Clp-Gly; (SEQ ID NO: 232)Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Met-Clp-Gly; (SEQ ID NO: 233)Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Met-Gly; (SEQ ID NO: 234)Met-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly; (SEQ ID NO: 235)Pro-Met-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly; (SEQ ID NO: 236)Pro-Clp-Gly-Met-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly; (SEQ ID NO: 237)Pro-Clp-Gly-Pro-Met-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly; (SEQ ID NO: 238)Pro-Clp-Gly-Pro-Clp-Gly-Met-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly; (SEQ ID NO: 239)Pro-Clp-Gly-Pro-Clp-Gly-Pro-Met-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly; (SEQ ID NO: 240)Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Met-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly; (SEQ ID NO: 241)Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Met-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly; (SEQ ID NO: 242)Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Met-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly; (SEQ ID NO: 243)Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Met-Gly-Pro-Clp-Gly-Pro-Clp-Gly; (SEQ ID NO: 244)Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Met-Clp-Gly-Pro-Clp-Gly; (SEQ ID NO: 245)Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Met-Gly-Pro-Clp-Gly; (SEQ ID NO: 246)Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Met-Clp-Gly; (SEQ ID NO: 247)Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Met-Gly; (SEQ ID NO: 248)Met-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly; (SEQ ID NO: 249)Clp-Met-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly; (SEQ ID NO: 250)Clp-Hyp-Gly-Met-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly; (SEQ ID NO: 251)Clp-Hyp-Gly-Clp-Met-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly; (SEQ ID NO: 252)Clp-Hyp-Gly-Clp-Hyp-Gly-Met-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly; (SEQ ID NO: 253)Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Met-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly; (SEQ ID NO: 254)Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Met-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly  (SEQ ID NO: 255)Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Met-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly; (SEQ ID NO: 256)Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Met-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly; (SEQ ID NO: 257)Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Met-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly; (SEQ ID NO: 258)Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Met-Hyp-Gly-Clp-Hyp-Gly; (SEQ ID NO: 259)Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Met-Gly-Clp-Hyp-Gly; (SEQ ID NO: 260)Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Met-Hyp-Gly; and (SEQ ID NO: 261)Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Met-Gly.

In certain other embodiments of the invention, the collagen mimeticpeptide may comprise, consist of or have an amino acid sequence that isor corresponds to a 21-mer of any one of SEQ ID NOs:1-9, in which atleast one lysine (Lys) residue has been substituted for at least one ofthe proline residues in SEQ ID NO:1, at least one of the hydroxyprolineresidues in SEQ ID NOs:2-3 and 6, at least one of the fluoroprolineresidues in SEQ ID NOs:4-6, or at least one of the chloroprolineresidues in SEQ ID NOs:7-9, yielding, for example, the followingsequences:

(SEQ ID NO: 262)Pro-Pro-Gly-Pro-Pro-Gly-Lys-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly; (SEQ ID NO: 263)Hyp-Pro-Gly-Hyp-Pro-Gly-Lys-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly; (SEQ ID NO: 264)Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Lys-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly; (SEQ ID NO: 265)Pro-Flp-Gly-Pro-Flp-Gly-Pro-Lys-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly; (SEQ ID NO: 266)Pro-Clp-Gly-Pro-Clp-Gly-Pro-Lys-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly; (SEQ ID NO: 267)Lys-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly; (SEQ ID NO: 268)Pro-Lys-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly; (SEQ ID NO: 269)Pro-Pro-Gly-Lys-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly; (SEQ ID NO: 270)Pro-Pro-Gly-Pro-Lys-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly; (SEQ ID NO: 271)Pro-Pro-Gly-Pro-Pro-Gly-Pro-Lys-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly; (SEQ ID NO: 272)Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Lys-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly; (SEQ ID NO: 273)Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Lys-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly; (SEQ ID NO: 274)Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Lys-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly; (SEQ ID NO: 275)Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Lys-Gly-Pro-Pro-Gly-Pro-Pro-Gly; (SEQ ID NO: 276)Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Lys-Pro-Gly-Pro-Pro-Gly; (SEQ ID NO: 277)Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Lys-Gly-Pro-Pro-Gly; (SEQ ID NO: 278)Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Lys-Pro-Gly; (SEQ ID NO: 279)Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Lys-Gly; (SEQ ID NO: 280)Lys-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly; (SEQ ID NO: 281)Hyp-Lys-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly; (SEQ ID NO: 282)Hyp-Pro-Gly-Lys-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly  (SEQ ID NO: 283)Hyp-Pro-Gly-Hyp-Lys-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly; (SEQ ID NO: 284)Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Lys-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly; (SEQ ID NO: 285)Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Lys-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly; (SEQ ID NO: 286)Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Lys-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly; (SEQ ID NO: 287)Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Lys-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly; (SEQ ID NO: 288)Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Lys-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly; (SEQ ID NO: 289)Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Lys-Pro-Gly-Hyp-Pro-Gly; (SEQ ID NO: 290)Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Lys-Gly-Hyp-Pro-Gly; (SEQ ID NO: 291)Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Lys-Pro-Gly  (SEQ ID NO: 292)Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Lys-Gly; (SEQ ID NO: 293)Lys-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly; (SEQ ID NO: 294)Pro-Lys-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly; (SEQ ID NO: 295)Pro-Hyp-Gly-Lys-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly; (SEQ ID NO: 296)Pro-Hyp-Gly-Pro-Lys-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly; (SEQ ID NO: 297)Pro-Hyp-Gly-Pro-Hyp-Gly-Lys-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly; (SEQ ID NO: 298)Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Lys-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly; (SEQ ID NO: 299)Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Lys-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly; (SEQ ID NO: 300)Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Lys-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly; (SEQ ID NO: 301)Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Lys-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly; (SEQ ID NO: 302)Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Lys-Hyp-Gly-Pro-Hyp-Gly; (SEQ ID NO: 303)Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Lys-Gly-Pro-Hyp-Gly; (SEQ ID NO: 304)Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Lys-Hyp-Gly; (SEQ ID NO: 305)Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Lys-Gly; (SEQ ID NO: 306)Lys-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly; (SEQ ID NO: 307)Pro-Lys-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly; (SEQ ID NO: 308)Pro-Flp-Gly-Lys-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly; (SEQ ID NO: 309)Pro-Flp-Gly-Pro-Lys-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly; (SEQ ID NO: 310)Pro-Flp-Gly-Pro-Flp-Gly-Lys-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly; (SEQ ID NO: 311)Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Lys-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly; (SEQ ID NO: 312)Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Lys-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly; (SEQ ID NO: 313)Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Lys-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly; (SEQ ID NO: 314)Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Lys-Gly-Pro-Flp-Gly-Pro-Flp-Gly; (SEQ ID NO: 315)Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Lys-Flp-Gly-Pro-Flp-Gly; (SEQ ID NO: 316)Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Lys-Gly-Pro-Flp-Gly; (SEQ ID NO: 317)Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Lys-Flp-Gly; (SEQ ID NO: 318)Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Lys-Gly; (SEQ ID NO: 319)Lys-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly; (SEQ ID NO: 320)Pro-Lys-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly; (SEQ ID NO: 321)Pro-Flp-Gly-Lys-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly; (SEQ ID NO: 322)Pro-Flp-Gly-Pro-Lys-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly; (SEQ ID NO: 323)Pro-Flp-Gly-Pro-Flp-Gly-Lys-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly; (SEQ ID NO: 324)Pro-Flp-Gly-Pro-Flp-Gly-Pro-Lys-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly; (SEQ ID NO: 325)Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Lys-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly; (SEQ ID NO: 326)Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Lys-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly; (SEQ ID NO: 327)Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Lys-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly; (SEQ ID NO: 328)Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Lys-Gly-Pro-Flp-Gly-Pro-Flp-Gly; (SEQ ID NO: 329)Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Lys-Flp-Gly-Pro-Flp-Gly; (SEQ ID NO: 330)Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Lys-Gly-Pro-Flp-Gly; (SEQ ID NO: 331)Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Lys-Flp-Gly; (SEQ ID NO: 332)Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Lys-Gly; (SEQ ID NO: 333)Lys-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly; (SEQ ID NO: 334)Flp-Lys-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly; (SEQ ID NO: 335)Flp-Hyp-Gly-Lys-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly; (SEQ ID NO: 336)Flp-Hyp-Gly-Flp-Lys-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly; (SEQ ID NO: 337)Flp-Hyp-Gly-Flp-Hyp-Gly-Lys-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly; (SEQ ID NO: 338)Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Lys-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly; (SEQ ID NO: 339)Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Lys-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly; (SEQ ID NO: 340)Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Lys-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly; (SEQ ID NO: 341)Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Lys-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly; (SEQ ID NO: 342)Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Lys-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly; (SEQ ID NO: 343)Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Lys-Hyp-Gly-Flp-Hyp-Gly; (SEQ ID NO: 344)Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Lys-Gly-Flp-Hyp-Gly; (SEQ ID NO: 345)Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Lys-Hyp-Gly; (SEQ ID NO: 346)Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Lys-Gly; (SEQ ID NO: 347)Lys-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly; (SEQ ID NO: 348)Pro-Lys-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly; (SEQ ID NO: 349)Pro-Clp-Gly-Lys-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly; (SEQ ID NO: 350)Pro-Clp-Gly-Pro-Lys-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly; (SEQ ID NO: 351)Pro-Clp-Gly-Pro-Clp-Gly-Lys-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly; (SEQ ID NO: 352)Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Lys-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly; (SEQ ID NO: 353)Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Lys-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly; (SEQ ID NO: 354)Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Lys-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly; (SEQ ID NO: 355)Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Lys-Gly-Pro-Clp-Gly-Pro-Clp-Gly; (SEQ ID NO: 356)Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Lys-Clp-Gly-Pro-Clp-Gly; (SEQ ID NO: 357)Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Lys-Gly-Pro-Clp-Gly; (SEQ ID NO: 358)Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Lys-Clp-Gly; (SEQ ID NO: 359)Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Lys-Gly; (SEQ ID NO: 360)Lys-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly; (SEQ ID NO: 361)Pro-Lys-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly; (SEQ ID NO: 362)Pro-Clp-Gly-Lys-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly; (SEQ ID NO: 363)Pro-Clp-Gly-Pro-Lys-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly; (SEQ ID NO: 364)Pro-Clp-Gly-Pro-Clp-Gly-Lys-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly; (SEQ ID NO: 365)Pro-Clp-Gly-Pro-Clp-Gly-Pro-Lys-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly; (SEQ ID NO: 366)Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Lys-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly; (SEQ ID NO: 367)Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Lys-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly; (SEQ ID NO: 368)Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Lys-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly; (SEQ ID NO: 369)Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Lys-Gly-Pro-Clp-Gly-Pro-Clp-Gly; (SEQ ID NO: 370)Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Lys-Clp-Gly-Pro-Clp-Gl; (SEQ ID NO: 371)Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Lys-Gly-Pro-Clp-Gly; (SEQ ID NO: 372)Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Lys-Clp-Gly; (SEQ ID NO: 373)Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Lys-Gly; (SEQ ID NO: 374)Lys-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly; (SEQ ID NO: 375)Clp-Lys-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly; (SEQ ID NO: 376)Clp-Hyp-Gly-Lys-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly; (SEQ ID NO: 377)Clp-Hyp-Gly-Clp-Lys-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly; (SEQ ID NO: 378)Clp-Hyp-Gly-Clp-Hyp-Gly-Lys-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly; (SEQ ID NO: 379)Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Lys-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly; (SEQ ID NO: 380)Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Lys-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly; (SEQ ID NO: 381)Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Lys-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly; (SEQ ID NO: 382)Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Lys-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly; (SEQ ID NO: 383)Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Lys-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly; (SEQ ID NO: 384)Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Lys-Hyp-Gly-Clp-Hyp-Gly; (SEQ ID NO: 385)Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Lys-Gly-Clp-Hyp-Gly; (SEQ ID NO: 386)Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Lys-Hyp-Gly; and (SEQ ID NO: 387)Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Lys-Gly.

Preferred CMPs according to this aspect of the invention include CMPshaving amino acid sequences corresponding to SEQ ID NOs:1-14, 66-94,107-135, 136-140, 192-220, 233-261, 260-264, 280, 281, 293, 294, 306,307, 318-346, 347, 348, and 359-387. Particularly preferred are CMPshaving amino acid sequences corresponding to SEQ ID NOs:1, 6, 9, 10-27,81-94, 122-135, 207-220, 248-261, 333-346 and 374-387. Even moreparticularly preferred are CMPs having amino acid sequencescorresponding to SEQ ID NOs:1, 6 and 9 (for CMPs that are not to bedirectly conjugated to one or more pharmaceutically active ingredientsor biologics), and CMPs having amino acid sequences corresponding to SEQID NOs: 10-27, 81-94, 122-135, 207-220, 248-261, 333-346 and 374-387(for CMPs that are to be directly conjugated to one or morepharmaceutically active ingredients or biologics). It will be understoodby those of ordinary skill, of course, based on knowledge in the art andthe teachings herein, that such CMPs may comprise two or more cysteine,methionine and/or lysine residues, in which at least one additionalcysteine, methionine and/or lysine residue, or any combination thereof,may be substituted for at least one proline residue, at least onehydroxyproline residue, at least one fluoroproline residue and/or atleast one chloroproline residue in any of the foregoing CMP sequencesthat comprise at least one proline, at least one hydroxyproline, atleast one fluoroproline and/or at least one chloroproline residue. Italso will be appreciated by those of ordinary skill in the art based onthe teachings herein and information readily available in the art thatother combinations of amino acid substitutions are also possible andwithin the scope of the present invention.

The CMPs described herein are suitable for a variety of purposes. Forexample, as described in further detail elsewhere herein, the CMPs maybe used in a variety of therapeutic applications or preventativeapplications by being directly applied to or introduced into the body ofa human or veterinary animal, particularly at sites of collagendisruption or potential collagen disruption, where the CMPs describedherein will localize directly to the site of collagen disruption, annealto disrupted collagen strands and stabilize the collagen structure suchthat it resists further disruption, and in some cases reform a nativecollagen triple helix in the site of collagen disruption. Suchapplications are useful in promoting the repair and strengthening ofdisrupted collagen in sites of injury or potential injury or disruption,for example in wounds or disorders (e.g., scarring, wrinkle formation,etc.) involving skin, tendon, ligament, cartilage, bone and othercollagen-containing structures and organs. The CMPs described hereinalso are useful in providing biocompatible coatings for certain medicaldevices, to promote the healing of injuries and disorders in areas ofthe body where such devices are used in treating or preventing certaindiseases, disorders and structural abnormalities or injuries in humansand veterinary animals, particularly those in which such diseases,disorders and structural abnormalities or injuries involve disruption ofcollagen and/or collagen-containing structures. The CMPs describedherein also are useful in providing a unique delivery vehicle suitablefor delivering a variety of therapeutic compounds, compositions andmedicaments to sites of disease, disorder and structural abnormality orinjury in humans and veterinary animals, particularly for use intreating, preventing or ameliorating diseases, disorders, medicalconditions and structural abnormalities or injuries in which collagendisruption is either the cause of, is associated with, or is colocalizedwith the site of the disease, disorder and structural abnormality orinjury. Other suitable uses of the CMPs described herein and used incertain aspects of the present invention will be readily apparent to theordinarily skilled artisan based on the disclosure herein andinformation that is readily available in the art.

In certain embodiments, the CMPs described herein are suitable forformation into a film, wafer, membrane or gel comprising one or more ofthe CMPs in a form suitable for introduction or implantation into ahuman or animal for therapeutic, preventative or diagnostic applicationssuch as those described herein and others that will be familiar to thoseof ordinary skill in the relevant arts. For example, films, wafers,membranes, spheres, nanoparticles or gels can be formed from a solutionof one or more of the CMPs described herein using methods such as thosedescribed in U.S. Pat. Nos. 6,197,934; 6,448,378; and 9,289,396; thedisclosures of all of which are incorporated herein by reference intheir entireties. Alternatively, films, wafers, membranes spheres,nanoparticles, or gels can be formed from other materials, such asatelocollagen (see U.S. Pat. Nos. 6,197,934; 6,448,378; and 9,289,396),copolymers of poly(lactic acid) and poly(glycoloic acid) (PLGA) (seeBala, I., et al., Crit. Rev. Ther. Drug Carrier Syst. 21(5):387-422(2004)), and other materials that are known to those of ordinary skillin the art (see, e.g., Kumar, V., et al., eds., “Polymer Gels:Perspectives and Applications”, ISBN 978-981-10-6079-3, Singapore:Springer (2018)), and one or more of the CMPs can be suitablyincorporated into such films, wafers, membranes, spheres, nanoparticles,gels, etc., during the formation thereof by including the CMPs in thesolution, at concentrations of about 1%-99%, about 2%-95%, about 3%-90%,about 4%-90%, about 5%-90%, about 10%-90%, about 15%-90%, about 20%-90%,about 25%-90%, about 25%-85%, about 25%-75%, about 25%-50%, about35%-50%, and the like. Suitable other amounts or concentrations of theCMPs described herein that can be suitably included in the solutionsduring formation of the films, wafers, membranes, spheres,nanoparticles, gels, etc., will be readily apparent from the teachingsherein and from information readily available in the art to theordinarily skilled artisan. In certain such embodiments, one or moretherapeutic compounds described herein, and/or one or more CMP-TCconjugates described herein, can be suitably incorporated into thesolution from which the films, wafers, membranes, spheres,nanoparticles, gels, etc., are formed. Alternatively, in relatedaspects, one or more films, wafers, membranes, spheres, nanoparticles,gels, etc., once formed as described above, can be treated or coatedwith one or more CMPs and/or CMP-TC conjugates described herein, byimmersing the films, wafers, membranes, spheres, nanoparticles, gels,etc., in a solution, particularly a buffered aqueous solution,containing a suitable amount or concentration (such as those describedherein) of one or more CMPs or CMP-TC conjugates described herein, andthen drying the films, wafers, membranes, etc., prior to use intherapeutic, preventative or diagnostic methods such as those describedherein.

Attachment/Conjugation of CMPs

In certain embodiments of the invention, the CMPs described herein aresuitably attached or conjugated to one or more therapeutic or diagnosticcompounds, to produce CMP conjugate compounds. In such embodiments ofthe invention, the CMP-therapeutic compound or CMP-diagnostic compoundconjugate compounds can then be introduced into the body of a human orveterinary animal, in methods of treating and/or preventing and/ordiagnosing certain diseases, disorders and structural abnormalities inhumans or veterinary animals suffering therefrom. Accordingly, incertain embodiments the present invention also provides the use of theCMPs described herein attached or conjugated to one or more therapeuticcompounds to produce conjugated CMPs, compositions comprising suchconjugated CMPs (which may optionally comprise one or more additionaltherapeutic or pharmaceutically active ingredients), methods ofproducing such conjugates and methods of using such conjugates andcompositions in the treatment, prevention and diagnosis of a variety ofdiseases, disorders and medical conditions in humans and veterinaryanimals.

Conjugates of CMPs and at least one therapeutic compound (which may bedescribed herein as “CMP-TC conjugates”) according to this aspect of theinvention will comprise at least one CMP described herein attached to atleast one therapeutic compound to form a CMP-TC conjugate. CMPs suitablyused in such aspects of the invention include any of those describedherein, including CMPs having an amino acid sequence corresponding toany one of SEQ ID NOs:1-387 and particularly wherein the CMPs have anamino acid sequence corresponding to any one of SEQ ID NOs:1-14, 66-94,107-135, 136-140, 192-220, 233-261, 260-264, 280, 281, 293, 294, 306,307, 318-346, 347, 348, and 359-387, and more particularly CMPs havingamino acid sequences corresponding to SEQ ID NOs:10-27, 81-94, 122-135,207-220, 248-261, 333-346 and 374-387. Other suitable CMP sequences willbe immediately apparent to one of ordinary skill in the art based on theteachings contained herein. For example, a CMP having at least one, andin some cases more than one, cysteine, methionine or lysine residuesubstituted in place of at least one, and in some cases more than one,proline, hydroxyproline, fluoroproline or chloroproline residue in SEQID NOs:1-9, will be particularly suitable for use in producing theCMP-TC conjugates provided by and used in the present invention.Examples of such suitable CMPs include those having amino acid sequencescorresponding to SEQ ID NOs: 10-27, 81-94, 122-135, 207-220, 248-261,333-346 and 374-387.

Methods of preparing the CMPs and CMP-TCs described herein and providedand used in the present invention will be familiar to those of ordinaryskill in the art based on the teachings herein and information that isreadily available in the art. For example, CMPs can be synthesized usingstandard protein/peptide synthesis techniques such as those described inU.S. Pat. Nos. 5,973,112; 7,122,521; and 7,858,741; as well as in U.S.Patent Publ. No. US 2007/0275897 A1, the disclosures of all of which areincorporated herein by reference in their entireties. Synthesis of CMPscan also be accomplished by purchasing custom-synthesized CMPs producedcommercially, for example by Bachem (Torrance, CA, USA) and RS Synthesis(Louisville, KY, USA). In other embodiments, synthesis of CMPs can beaccomplished using genetic engineering and recombinant expression of theCMPs from prokaryotic or eukaryotic expression systems (see, e.g.,Buechter, D. D., et al., J. Biol. Chem. 278(1):645-650 (2003)).

In synthesizing the peptides described herein, in certain embodiments itis preferred that certain stereochemistries be used for the amino acidsubstitutions, particularly if hydroxyproline, fluoroproline orchloroproline are used:

-   -   (1) if hydroxyproline is substituted in place of proline in the        Xaa position of the Xaa-Yaa-Gly trimer noted hereinabove, in        certain embodiments the hydroxyproline has a (2R, 4S)        stereochemistry, or a cis or trans, and preferably a cis,        stereochemistry;    -   (2) if hydroxyproline is substituted in place of proline in the        Yaa position of the Xaa-Yaa-Gly trimer noted hereinabove, in        certain embodiments the hydroxyproline has a (2R, 4S)        stereochemistry, or a cis or trans, and preferably a cis,        stereochemistry;    -   (3) if fluoroproline is substituted in place of proline in the        Yaa position of the Xaa-Yaa-Gly trimer noted hereinabove, in        certain embodiments the hydroxyproline has a (2R, 4S)        stereochemistry, or a cis or trans, and preferably a cis,        stereochemistry; and    -   (4) if chloroproline is substituted in place of proline in the        Yaa position of the Xaa-Yaa-Gly trimer noted hereinabove, in        certain embodiments the hydroxyproline has a (2R, 4S)        stereochemistry, or a cis or trans, and preferably a cis,        stereochemistry.

Other suitable stereochemistries can be determined empirically withouthaving to resort to undue experimentation, and will be immediatelyapparent to those of ordinary skill in the art. As noted above, certainCMPs provided by and used in the present invention may contain one ormore additional substitutions, for example one or more cysteine residuesand/or one or more methionine residues, in place of one or more prolinesin a given CMP multimer. Such substitutions are suitably accomplished byadding those residues to the growing CMP peptide chain during thesynthetic process using standard peptide synthetic methods such as thosedescribed elsewhere herein and those that are known in the art.

Once the CMPs have been prepared, they are suitably used in producingthe CMP-TCs of the invention, i.e., the therapeutic or diagnosticcompositions of the invention, by attaching one or more therapeuticcompounds to the CMPs. In certain embodiments, the CMP-TCs of theinvention can be prepared a method comprising (a) providing a collagenmimetic peptide having an amino acid sequence corresponding to any oneof SEQ ID NOs:1-387, particularly CMPs have an amino acid sequencecorresponding to any one of SEQ ID NOs:1-14, 66-94, 107-135, 136-140,192-220, 233-261, 260-264, 280, 281, 293, 294, 306, 307, 318-346, 347,348, and 359-387, and more particularly CMPs having amino acid sequencescorresponding to SEQ ID NOs:10-27, 81-94, 122-135, 207-220, 248-261,333-346 and 374-387; (b) providing at least one therapeutic ordiagnostic compound suitable to be conjugated to the CMP; and (c)attaching the therapeutic or diagnostic compound directly or indirectlyto the CMP. In certain cases, particularly wherein the therapeuticcompound is a small peptide biologic compound, the therapeutic compoundcan be directly attached to the CMP via a peptide bond, for example bysimply extending the synthesis of the peptide beyond the carboxyterminus of the CMP and attaching the amino terminal amino acid of thetherapeutic compound to the carboxy terminal amino acid of the CMP via apeptide bond. One example of such a CMP-TC is a peptide conjugate inwhich the wound healing peptide known as Substance P and having an aminoacid sequence of Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met (SEQ IDNO:388), is attached to a CMP described herein. Examples of suchconjugates include, for example:

(SEQ ID NO: 389)Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met; (SEQ ID NO: 390)Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met;(SEQ ID NO: 391)Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met;(SEQ ID NO: 392)Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met;(SEQ ID NO: 393)Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met;(SEQ ID NO: 394)Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met; and(SEQ ID NO: 395)Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met.

In other methods of the invention, the one or more therapeutic ordiagnostic compounds are suitably conjugated or attached to the CMPs viaa covalent bond other than a peptide bond. For example, therapeuticcompounds can be attached directly to a cysteine or methionine residueon a CMP described herein by covalently bonding a hydroxyl or aminogroup on an amino acid residue (e.g., a lysine residue) on thetherapeutic or diagnostic compound (if it is a biologic molecule) to asulfhydryl group on the cysteine or methionine residue of the CMP.Alternatively, if the CMP does not contain a cysteine or methionineresidue, the one or more therapeutic or diagnostic compounds can beattached or conjugated to the CMP by a reaction between a hydroxyl groupor amino group on the CMP and a sulfhydryl group on an amino acidresidue (e.g., at a cysteine or methionine residue) on the therapeuticor diagnostic compound (if it is a biologic molecule). In yet anotheralternative method of conjugation, therapeutic compounds can be attacheddirectly to a lysine residue on a CMP described herein by covalentlybonding the therapeutic compound to an amino group on the lysine, forexample using NHS ester conjugation (see, e.g., Mattson, G., et al.,Molec. Biol. Rep. 17:167-183 (1993); Grabarek, Z. and Gergely, J., Anal.Biochem. 185:131-135 (1990); Staros, J. V. et al., Anal. Biochem.156:220-2 (1986); Timkovich, R., Anal. Biochem. 79:135-43 (1977)). Suchdirect covalent attachments or conjugations between the CMP and thetherapeutic/diagnostic compound can be accomplished using standardreaction techniques that will be familiar to those of ordinary skill inorganic chemistry.

In other embodiments, particularly those wherein the therapeutic ordiagnostic compound is not a biologic (and therefore does not have apeptide structure or amino acid residues having groups suitablyattachable to cysteine, methionine, lysine or other residues on theCMP), such as small molecule organic or inorganic therapeutic ordiagnostic compounds, the at least one therapeutic or diagnosticcompound is indirectly attached to the collagen mimetic peptide via useof an attachment means. In such embodiments, the attachment means hastwo attachable ends, one of which attaches to an amino acid residue, andsuitably a sulfhydryl group on a cysteine or methionine residue or anamino group on a lysine residue, of a CMP, and the other of whichattaches to a hydroxyl or amino group on the therapeutic or diagnosticcompound. For example, in certain such embodiments the attachment meanscomprises at least one polymeric chain having a first end and a secondend, and the first end of the polymeric chain binds to the sulfhydrylgroup on a cysteine or methionine residue or an amino group on a lysineresidue on the collagen mimetic peptide and the opposite or second endof the polymeric chain binds to an amino group or hydroxyl group on thetherapeutic compound. In embodiments where the therapeutic or diagnosticcompound is a biologic that is not suitable for direct attachment viapeptide synthesis as described elsewhere herein, the second end of theattachment means can be attached to an amino group on an amino acidresidue, such as a lysine residue, on the biologic therapeutic ordiagnostic compound. Suitable such attachment means are well-known tothose of ordinary skill in the art. For example, one attachment meanssuitable for use in accordance with this aspect of the inventionincludes a moiety which is a polymeric chain that on one end (theCMP-binding end in particular) comprises a sulfhydryl-binding group suchas a maleimide, and on the other end (the therapeutic or diagnosticcompounding-binding end in particular) comprises an amino-binding groupsuch as N-hydroxysuccinimide. In certain such embodiments, the polymericchain is a linear polyethyleneglycol chain comprising at least fourethyleneglycol monomers, e.g., from four to fifty ethyleneglycolmonomers, from ten to forty ethyleneglycol monomers, from fifteen tothirty ethyleneglycol monomers, from fifteen to twenty-fiveethyleneglycol monomers, from twenty to twenty-five ethyleneglycolmonomers, and particularly four, six, eight, twelve, twenty, twenty-two,twenty-three, twenty-four or twenty-five ethyleneglycol monomers. Suchattachment means suitable for attaching one or more therapeutic ordiagnostic compounds to a CMP by the methods described herein areavailable commercially, e.g., from Thermo Fisher Scientific (Waltham,MA) (e.g., SM(PEG)6, SM(PEG)8, SM(PEG)12 and SM(PEG)24). By adjustingthe length of the polymer chain, the bioavailability and sustainabilityof the therapeutic or diagnostic compound in vivo can be modulated—theuse of longer polymer chains, e.g., a polymer comprising 24ethyleneglycol monomers, will increase the rate of bioavailability ofthe compound once the CMP-TC has been introduced into the body of thehuman or veterinary animal, while the use of shorter polymer chains,e.g., a polymer comprising six ethyleneglycol monomers, will decreasethe rate of bioavailability and thus increase the sustainability (or, inother words, will result in delayed release or sustained release) of thetherapeutic or diagnostic compound. Hence, according to certain suchaspects of the invention, the at least one therapeutic compoundcomprises at least one reactive hydroxyl group capable of beingcross-linked to the collagen mimetic peptide using a polymeric linker.

Other indirect attachment methods for conjugating the one or moretherapeutic or diagnostic compounds into or onto the CMPs also aresuitably used according to the invention. For example, the at least onetherapeutic or diagnostic compound can be enclosed within at least onenanoparticle that is attached via an attachment means, such as thosedescribed herein, to the collagen mimetic peptide. Alternatively, thecollagen mimetic peptide can suitably comprise at least one biotinmoiety and the therapeutic molecule can suitably comprise at least oneavidin or streptavidin moiety, and the biotin moiety on the collagenmimetic peptide will bind to the avidin or streptavidin moiety on thetherapeutic or diagnostic compound, thereby attaching the collagenmimetic peptide to the therapeutic or diagnostic compound. Of course,the alternative is also suitable for use, in which the collagen mimeticpeptide can suitably comprise at least one avidin or streptavidin moietyand the therapeutic or diagnostic compound can suitably comprise atleast one biotin moiety, and the biotin moiety on the at least onetherapeutic or diagnostic compound will bind to the avidin orstreptavidin moiety on the collagen mimetic peptide, thereby attachingthe collagen mimetic peptide to the therapeutic compound.

Thus, according to certain embodiments of the invention, the therapeuticor diagnostic compounds can be suitably attached directly to the CMPsdescribed herein. In other embodiments of the invention, the one or moretherapeutic or diagnostic compounds can be attached indirectly to theCMPs described herein, for example via the use of a spacer, linker orbridge moiety. It is to be understood that whether the one or moretherapeutic compounds are attached directly or indirectly to the CMPs,such attachment results in the production of conjugates of the CMPs andthe one or more therapeutic compounds, which may be defined herein asCMP-TC conjugates.

Suitable therapeutic or diagnostic compounds for attachment orconjugation to the CMPs to produce the CMP-TCs of the present inventioninclude any compound that has been shown to have particular therapeuticor preventative properties against one or more diseases, disorders,physical conditions or afflictions when introduced into a human orveterinary animal suffering from or predisposed to such diseases,disorders, physical conditions or afflictions. Provided that thetherapeutic or diagnostic compound is capable of being conjugated orattached to at least one CMP according to the teachings herein, anytherapeutic or diagnostic compound can be used in the conjugates,compositions and methods of the present invention. Suitable suchtherapeutic compounds may be biologic or non-biologic (e.g., so-called“small molecule”) therapeutic compounds. Compounds suitable for useinclude, but are not limited to, a steroidal anti-inflammatory drug,(e.g., prednisolone or a pharmaceutically acceptable salt thereof, suchas prednisolone acetate), a nonsteroidal anti-inflammatory drug (e.g.,acetylsalicylic acid, acetaminophen, ibuprofen, naproxen, nepafenac,bromfenac, diclofenac, flurbiprofen, ketoprofen, and ketorolac, andpharmaceutically acceptable salts, esters and derivatives thereof), atopical anesthetic (e.g., tetracaine, lidocaine, oxybuprocaine,proparacaine, and the like), a vitamin or a vitamin derivative orvitamin precursor (e.g., retinol, tretinoin, retinal, carotene and otherretinoids and retinoid derivatives or precursors; folate; α-tocopherol;calciferol; phylloquinone, menadione and other vitamin K forms,precursors or derivatives, ascorbate; and the like), a therapeuticenzyme or a therapeutic fragment thereof (e.g., a collagenase and aserine protease, or a therapeutically effective fragment thereof), anantibiotic (e.g., an aminoglycoside antibiotic (such as gentamycin,tobramycin, paromomycin, kanamycin, neomycin and amikacin, and apharmaceutically acceptable salt or ester thereof, e.g., tobramycinsulfate), a fluoroquinolone antibiotic (such as moxifloxacin,gatifloxacin, levofloxacin, gemifloxacin, ciprofloxacin, norfloxacin andofloxacin, and a pharmaceutically acceptable salt, ester or derivativethereof, e.g., moxifloxacin hydrochloride, ciprofloxacin hydrochlorideand gatifloxacin hydrochloride), a sulfonamide antibiotic (such assulfacetamide, sulfadiazine, sulfadimidine, sulfafurazole(sulfisoxazole), sulfisomidine (sulfaisodimidine), sulfadoxine,sulfamethoxazole, sulfamoxole, sulfanitran, sulfadimethoxine,sulfamethoxypyridazine, sulfametoxydiazine, sulfametopyrazine andterephtyl, and a pharmaceutically acceptable salt, ester or derivativethereof), a β-lactam antibiotic (such as a penicillin or a derivativethereof (for example penicillin G, penicillin V, a benzylpenicillin andphenoxymethylpenicillin), dicloxacillin, flucloxacillin, oxacillin,nafcillin, amoxicillin, an ampicillin, ticarcillin, piperacillin,ritipenem, a carbapenem (e.g., ertapenem, doripenem, imipenem andmeropenem, and a pharmaceutically acceptable salt, ester or derivativethereof), a cephem (such as cefazolin, cefalexin, cefadroxil, cefapirin,cefaclor, cefotetan, cephamycin (cefoxitin), cefprozil, cefuroximeaxetil, ceftriaxone, ceftazidime, cefoperazone, cefdinir, cefcapene,cefdaloxime, ceftizoxime, cefmenoxime, cefotaxime, cefpiramide,cefpodoxime, ceftibuten, cefditoren, cefepime, ceftaroline fosamil,ceftolozane, ceftobiprole, ceftiofur, cefquinome and cefovecin, and apharmaceutically acceptable salt, ester or derivative thereof), amonobactam (such as aztreonam or a pharmaceutically acceptable salt,ester or derivative thereof) and a β-lactamase inhibitor (such assulbactam, tazobactam, clavulanic acid and avibactam, and apharmaceutically acceptable sat, ester or derivative thereof)) or acyclic peptide antibiotic (such as cyclosporine), a therapeuticmonoclonal antibody or a therapeutic fragment thereof (such asadalimumab, altumomab, atezolizumab, atlizumab, bevacizumab,canakinumab, catumaxomab, certolizumab, cetuximab, clivatuzumab,edrecolomab, efalizumab, fontolizumab, girentuximab, golimumab,infliximab, labetuzumab, MABp1 (Xilonix™), natalizumab, nimotuzumab,nivolumab, oregovomab, panitumumab, pembrolizumab, pemtumomab,pertuzumab, ramucirumab, ranibizumab, rituximab, ruplizumab,tracatuzumab, tocilizumab, trastuzumab, ustekinumab, vedolizumab,visilizumab, votumumab, zalutumumab and zanolimumab, and activefragments, combinations or conjugates thereof), a therapeutic fusionprotein (in certain embodiments, a recombinant fusion protein such asaflibercept (Regeneron), etanercept (Amgen), alefacept (AstellasPharma), abatacept (Bristol-Myers Squibb), rilonacept (Regeneron),romiplostim (Amgen) and belatacept (Bristol-Myers Squibb)), aprostaglandin analogue (such as latanoprost, travoprost, tafluprost,unoprostone, netarsudil, tatanoprostene bunod, netarsudil andbimatoprost, and pharmaceutically acceptable salts, esters andderivatives thereof), a growth factor (such as EGF, PDGF, TGF-β, IGF-1,VEGF, FGF-β, IGF-1) or a therapeutic or growth-promoting (particularlyskin growth-promoting) fragment thereof, a neuropeptide (such asSubstance P (SEQ ID NO:388), an α-adrenergic antagonist (such asbrimonidine, clonidine and apraclonidine, and pharmaceuticallyacceptable salts, esters or derivatives thereof), a β-adrenergicantagonist (such as timolol, propranolol, atenolol, levobunolol,carteolol, betaxolol, and pharmaceutically acceptable salts, esters andderivatives thereof, e.g., timolol maleate), a cell surface receptorantagonist (such as lifitegrast or etanercept), a carbonic anhydraseinhibitor (such as dorzolamide, brinzolamide, methazolamide andacetazolamide, and pharmaceutically acceptable salts, esters andderivatives thereof, e.g., dorzolamide hydrochloride), andpharmaceutically acceptable salts, esters and derivatives thereof. Withcertain such therapeutic compounds, administration simultaneously withthe CMPs described herein, whether as a CMP-TC conjugate or simply withone or more CMPs and one or more TCs in an admixture or appliedseparately, may prevent, attenuate or lessen one or more adverse sideeffects of the therapeutic compound. For example, it is known that thetherapeutic administration of certain fluoroquinolone antibiotics maycause damage to collagen and collagen-containing structures (e.g.,tendons) in humans or veterinary animals who have been treated withfluoroquinolones (see, e.g., “FDA Drug Safety Communication: FDA updateswarnings for oral and injectable fluoroquinolone antibiotics due todisabling side effects,” accessed Nov. 6, 2017, atfda.gov/Drugs/DrugSafety/ucm511530.htm). As a result, simultaneous orco-administration of one or more of the CMPs described herein with oneor more fluoroquinolone antibiotics to a human or veterinary animal inneed of treatment with fluoroquinolones may allow the patient to receivethe therapeutic benefits of the fluoroquinolone while mitigating,ameliorating or avoiding the collagen disruption resulting from suchtherapy, as the CMP can localize to and repair areas of damaged collagenin vivo.

Other suitable therapeutic compounds for use in the CMP-TC compounds,compositions and conjugates of the present invention include othernon-biologic small molecule therapeutic compounds, including but notlimited to alkylating agents, anti-tumor antibiotics, antimetabolites,hormonal agents, plant alkaloids, angiogenesis inhibitor, GnRH agonists,tyrosine kinase inhibitors, and the like. Examples of such non-biologicsmall molecule therapeutic compounds suitably used in accordance withthe invention include but are not limited to a nitrosourea, alenalidomide, imatinib, penatrexed, bortexomib, abiraterone acetate,everolimus, taxol, docetaxel, paclitaxel, carbazitaxel, mitoxantrone,carboplatin, cisplatin, gemcitabine, doxorubicin, casodex, flutamide,enzalutamide, abiraterone, sipuleucel-T and ketoconazole. Other suitablenon-biologic small molecule therapeutic compounds that areadvantageously used in forming the CMP-TC conjugates of the presentinvention, particularly for producing CMP-TC conjugates that are usefulin treating certain cancers and preventing tumor metastasis, includeinhibitors of lysyl oxidase (LOX), lysyl oxidase-like 1 (LOXL1) andlysyl oxidase-like 2 (LOXL2) enzymes. Such inhibitors have beensuggested to have potential therapeutic application in treating and/orpreventing certain cancers and the metastasis of solid tumors (see,e.g., U.S. Pat. Nos. 5,201,456; 5,120,764; 5,252,608; 8,461,303;8,658,167; 8,680,246; 9,176,139; 9,255,086; and 9,289,447; see alsoErler, J. T., et al., Nature 440:1222-1226 (2006); Erler, J. T., et al.,Cancer Cell 15(1):35-44 (2009); Bondareva, A., et al., PLoS ONE4(5):e5620 (2009); Granchi, C., et al., ChemMedChem 4(10:1590-1594(2009); and Fang, M., et al., Tumor Biol. 35:2871-2882 (2014); thedisclosures of all of which are incorporated herein by reference intheir entireties). In related aspects of the invention, CMP-TCconjugates comprising one or more inhibitors of LOX or LOX-like enzymesare suitably used in treating and/or preventing certain fibroticdiseases and disorders that are mediated by oxidoreductase enzymes suchas LOX and the LOX-like enzymes (e.g., LOXL1 and LOXL2) in humans andveterinary animals. Fibrotic diseases and disorders suitably treatedand/or prevented according to this aspect of the invention include butare not limited to pulmonary fibrosis, liver cirrhosis, myocardialfibrosis, surgical scarring, systemic sclerosis, scleroderma, keloidformation, proliferative vitreo retinopathy, and other fibrotic diseasesand disorders that will be familiar to those of ordinary skill in therelevant arts. Particularly useful inhibitors of LOX and the Lox-likeproteins include β-aminopropionitrile and certain derivatives andprodrugs thereof (see, e.g., U.S. Pat. Nos. 5,201,456; 5,120,764;5,252,608; 8,461,303; 8,680,246; 9,176,139; and 9,255,086; thedisclosures of all of which are incorporated herein in theirentireties), as well as antibodies (which may be polyclonal or,preferably monoclonal) and fragments or portions thereof which bind toand inhibit the activity or function of LOX and LOX-like enzymes (see,e.g., U.S. Pat. No. 8,461,303; the disclosure of which is incorporatedherein in its entirety).

Suitable diagnostic compounds for attachment or conjugation to CMPs toproduce the conjugates and compositions of the invention include, butare not limited to, labeled probes, such as fluorescent dyes (e.g.,quantum dots, indocyanine green, fluorescein, rhodamine, a merocyaninedye, a near-infrared fluorescent dye, and the like); a radioisotope, anuclide used for PET, a nuclide used for SPECT, particularly whereineach of the radioisotope, the nuclide used for PET or SPECT is selectedfrom the group consisting of ¹¹C, ¹³N, ¹⁵O, ¹⁸F, ⁶⁶Ga, ⁶⁷Ga, ⁶⁸Ga, ⁶⁰Cu,⁶¹Cu, ⁶²Cu, ⁶⁷Cu, ⁶⁴Cu, ⁴⁸V, Tc-99 m, ²⁴¹Am, ⁵⁵Co, ⁵⁷Co, ¹⁵³Gd, ¹¹¹In,¹³³Ba, ⁸²Rb, ¹³⁹Ce, Te-123m, ¹³⁷Cs, ⁸⁶Y, ⁹⁰Y, ^(185/187)Re,^(186/188)Re, ¹²⁵I, a complex thereof, and a combination thereof; and anMill contrast medium, a CT contrast medium, and a magnetic material,particularly wherein each of the Mill contrast medium, the CT contrastmedium, and the magnetic material is selected from the group consistingof gadolinium, Gd-DTPA, Gd-DTPA-BMA, Gd-HP-DO3A, iodine, iron, ironoxide, chromium, manganese, a complex or chelate complex thereof, and acombination thereof. According to such aspects of the invention, the CMPand the labeled probe are suitably physically or chemically bounddirectly to each other, for example via a direct conjugation through acoordinate bond, a covalent bond, a hydrogen bond, a hydrophobicinteraction or a physical adsorption, or indirectly via use of at leastone attachment means such as those described herein and others that areknown in the art. Methods of conjugating or attaching diagnosticcompounds to proteins, such as CMPs, are known in the art (see, e.g.,U.S. Publ. Patent Appl. No. US 2012/0195828 A1, the disclosure of whichis incorporated herein in its entirety).

Use of CMPs and CMP-TC Conjugates

Thus, the invention provides methods of preparing compositions that areuseful in treating, preventing, diagnosing or ameliorating a disease,disorder or medical condition in humans or veterinary animals. In yetanother aspect, the invention provides methods of treating, preventing,diagnosing or ameliorating a disease, disorder or medical or physicalcondition in humans or veterinary animals using the compositions of theinvention. Particularly preferred CMPs for use in such aspects of theinvention include CMPs comprising, consisting essentially of, orconsisting of, CMPs having an amino acid sequence of (Pro-Pro-Gly)₇ (SEQID NO:1), (Flp-Hyp-Gly)₇ (SEQ ID NO:6) or (Clp-Hyp-Gly)₇ (SEQ ID NO:9),and derivatives thereof comprising one or more cysteine, methionine orlysine residues such as those described elsewhere herein.

The CMPs and CMP-TC conjugates of the present invention, includingsolutions, gels, films, wafers, membranes, spheres, nanoparticles andsuspensions comprising, consisting essentially of or consisting of theCMPs and/or CMP-TC conjugates of the present invention, are suitablyused as or included in compositions for use in, or as, a medicament fortreating, preventing or ameliorating a variety of diseases or disordersin humans or veterinary animals in need of treatment or preventionthereof. Other compositions provided by this aspect of the inventionprovide the use of CMPs conjugated to one or more diagnostic compoundsor molecules, such as one or more labeled probes, which then are used asdiagnostic reagents in a variety of tests and assays, particularly invivo or in situ, to diagnose a disease, disorder, or physical conditionin a human or veterinary animal. Such medicament compositions ordiagnostic compositions may comprise, in addition to the CMPs, CMP-TCconjugates or CMPs conjugated to one or more diagnostic compounds ormolecules, one or more additional therapeutic compounds orpharmaceutically active ingredients (e.g., one or more antibiotics, oneor more growth factors, autologous plasma rich in growth factors (PRGF),one or more cytokines, one or more antibodies fragments thereof, one ormore non-biologic small molecule therapeutic compounds, andpharmaceutically active salts, esters and derivatives thereof, and thelike, including those described herein and others that are known in theart. The compositions of the invention may additionally or alternativelycomprise one or more pharmaceutically acceptable carriers or excipients.Pharmaceutically acceptable carriers or excipients suitable for use inthe compositions and methods of the invention include, for example, oneor more solvents (which may include water, an organic solvent or aninorganic solvent), one or more buffers, one or more polymers, one ormore salts, one or more sugars, one or more sugar alcohols, one or moredisintegrating agents, one or more aerosolizing agents or carriers, oneor more dessicants, and the like. Other pharmaceutically acceptablecarriers or excipients suitable for use in the compositions of thepresent invention will be readily familiar to those of ordinary skill inthe relevant arts.

Diseases, disorders, physical conditions and medical conditions suitablytreated, prevented, ameliorated or diagnosed using the compositions andmethods of the invention include, but are not limited to ocular diseasesor disorders, skin diseases or disorders, cancers, gastrointestinaldiseases or disorders, genitourinary tract diseases or disorders,fibrotic diseases or disorders, cardiovascular diseases or disorders,bone diseases or disorders and rheumatic diseases or disorders.

Ocular diseases or disorders that can be treated, prevented, amelioratedor diagnosed using the compositions and methods of the invention includebut are not limited to glaucoma, cataracts, vitreous adhesions orfloaters, macular degeneration, dry eye syndrome, corneal keratitis,non-infectious corneal ulceration, non-infectious corneal melting,infectious corneal ulceration, infectious corneal melting,conjunctivitis, Stevens-Johnson Syndrome, scleritis, episcleritis,ectasia, keratoconus, corneal lacerations, corneal erosion, cornealabrasions, and post-operative afflictions of the eye resulting from eyesurgery. Such post-operative afflictions of the eye resulting from eyesurgery can be, for example, afflictions arising post-operatively fromcataract surgery or glaucoma surgery, particularly wherein thoseafflictions result in or are a post-operative state of the eye requiringmedication.

According to this aspect of the invention, methods of treating orpreventing an ocular disease, disorder or wound in a human or veterinaryanimal suffering from or predisposed to an ocular disease, disorder orwound, comprise administering the compositions described herein,particularly the CMPs or CMP-TC conjugates and/or compositionscomprising such conjugates, to an eye of a human or veterinary animal.Without wishing to be bound by theory, the inventors surmise that inareas of eye disease or disorder there is sufficient disruption of typeI collagen such that the CMP will target the site of the eye disease ordisorder specifically and intercalate into the collagen structure,thereby delivering the therapeutic compound to the site where it mustact to treat, prevent or ameliorate the eye disease or disorder. Theconjugates or compositions are suitably applied to the eye in a dosagesufficient to treat or prevent the ocular disease, disorder or wound,and the condition of the eye in said human or veterinary animal is thenmonitored over time for improvement in the disease state or physicalcondition. If necessary, the conjugate or composition of the inventionis then periodically readministered to the eye, according to dosing andtreatment schedules and protocols described herein and others that willbe familiar to the ordinarily skilled artisan, until the ocular disease,disorder or wound is cured, prevented or ameliorated. In suchembodiments, the conjugates or compositions of the invention can besuitably administered to the eye conjunctivally or subconjunctivally,particularly by administering the conjugate or composition into thesubconjunctival fornix. Administration of the conjugates or compositionsto the eye can be accomplished by any well-known means, includingapplying the conjugates or compositions to the eye in the form of one ormore drops or aliquots of a solution, a gel or a suspension thatcontains the composition or conjugates; via injection; in the form of asolid material such as a wafer or film (such as those described herein)that is implanted into an eye structure; in the form of a mesh or patch;by attaching the conjugate or composition to, or enclosing it within,one or more gels, spheres or nanoparticles that are then delivered intoan eye structure. Other suitable methods of applying the conjugates orcompositions to the eye to accomplish the therapeutic and diagnosticmethods of the invention will be readily apparent to the ordinarilyskilled artisan.

Skin diseases or disorders that can be treated, prevented, amelioratedor diagnosed using the compositions and methods of the invention includebut are not limited to skin wounds, scarring, wrinkles, “crepey skin”,skin cancer (e.g., melanomas, skin carcinomas, skin sarcomas,histiocytomas) and skin burns, including sunburn. Other skin diseases ordisorders suitably treated, prevented, ameliorated or diagnosedaccording to the invention include psoriasis and eczema, shingles,irritant contact dermatitis and allergic contact dermatitis (such aspoison ivy, poison oak or poison sumac).

According to this aspect of the invention, methods of treating orpreventing a skin disease, disorder or wound in a human or veterinaryanimal suffering from or predisposed to a skin disease, disorder orwound, comprise administering the compositions described herein,particularly the CMPs and CMP-TC conjugates, and compositions comprisingsuch CMPs and CMP-TC conjugates, to the skin of a human or veterinaryanimal at a site proximal to the location of a lesion associated with orcausing the skin disease, wound or disorder. Without wishing to be boundby theory, the inventors surmise that in areas of skin disease ordisorder there is sufficient disruption of type I collagen such that theCMP will target the site of the skin disease or disorder specificallyand intercalate into the collagen structure, thereby delivering the CMPand/or therapeutic compound to the site where it must act to treat,prevent or ameliorate the skin disease or disorder. Alternatively, thedisease or disorder afflicting the skin can be excised or resected fromthe skin (e.g., via surgical removal, for example of a skin cancer), andthe skin wound resulting from such excision or resection can be treatedwith one or more compositions of the invention according to the methodsdescribed herein. In certain embodiments, one or more of the CMPsthemselves, or one or more CMP-TC conjugates, or any combinationthereof, can be introduced into the skin, particularly intraepidermally,intradermally or subcutaneously, in the form of a so-called“cosmeceutical” (see, e.g., Epstein, H., Clin. Dermatol. 27(5):453-460(2009)). Particularly preferred CMP-TC conjugates or compositions foruse in such aspects of the invention include those wherein thetherapeutic compound is Substance P (SEQ ID NO:388), particularly thosewherein the CMP-TC conjugate has an amino acid sequence corresponding toany one of SEQ ID NOs: 389-395. Additional particularly preferred CMP-TCconjugates or compositions for use in such aspects of the inventioninclude those wherein the therapeutic compound is retinol or aderivative or precursor thereof. Additional preferred compositionscomprise such compositions that comprise or further comprise at leastone growth factor, at least one antibiotic, at least one antifungalcompound or at least one antiviral compound. Suitable growth factors,antibiotics, antifungal compounds and antiviral compounds include thosedescribed herein and others that are well-known in the dermatologicaland other relevant arts. According to this aspect of the invention, theconjugates or compositions are suitably applied to or into the skin in adosage sufficient to treat or prevent the skin disease, disorder orwound, and the condition of the skin in said human or veterinary animalis then monitored over time for improvement in the disease state orphysical condition. If necessary, the conjugate or composition of theinvention is then periodically readministered to or into the skin,according to dosing and treatment schedules and protocols describedherein and others that will be familiar to the ordinarily skilledartisan, until the skin disease, disorder or wound is cured, preventedor ameliorated. In such embodiments, the conjugates or compositions ofthe invention are suitably administered to or into the skin topically,intraepidermally, intradermally or subdermally. Administration of theconjugates or compositions to or into the skin can be accomplished byany well-known means, including in the form of a solution, an ointment,a salve, a patch, a cream, a topical solution and a drug eluting wafer.For example, the conjugates or compositions can be applied to orintroduced into the skin in the form of one or more drops of solution ora suspension that contains the composition or conjugates; via injection;in the form of a coating on a solid material that is implanted into theskin; in the form of a mesh or patch; by attaching the conjugate orcomposition to, or enclosing it within, one or more nanoparticles thatare then delivered into the skin. Other suitable methods of applying theconjugates or compositions to or into the skin to accomplish thetherapeutic and diagnostic methods of the invention will be readilyapparent to the ordinarily skilled artisan.

Cancers that can be treated, prevented, ameliorated or diagnosed usingthe compositions and methods of the invention include but are notlimited to skin cancers (e.g., those described elsewhere herein),intraluminal cancers and brain cancers. Intraluminal cancers suitablytreated, prevented, diagnosed or ameliorated using the conjugates,compositions and methods of the invention include but are not limited tocolorectal cancer, intestinal cancer, duodenal cancer, stomach cancer,pancreatic cancer, esophageal cancer, a bladder cancer (e.g.,non-muscle-invasive bladder cancer or carcinoma in situ of the bladder),a cancer of the upper urinary tract, alternatively referred to and alsoknown to those of ordinary skill as the renal pelvis (e.g., upper tracturothelial carcinoma, Wilms tumor and renal cancer), vaginal cancer,cervical cancer, uterine cancer, ovarian cancer, luminal breast cancerand lung cancer. Brain cancers suitably treated, prevented, diagnosed orameliorated using the conjugates, compositions and methods of theinvention include but are not limited to gliomas, glioblastomas,meningiomas, pituitary tumors, craniopharyngioma and hemangioblastomas.Other non-luminal cancers are also suitably treated, prevented,diagnosed or ameliorated using the conjugates, compositions and methodsof the invention, including but not limited to prostate cancer,testicular cancer, non-luminal breast cancer, bone cancer, head and neckcancer, thyroid cancer, liver cancer, sarcomas (e.g., Kaposi sarcoma,Ewing sarcoma, osteosarcoma, soft tissue sarcoma and rhabdomyosarcoma),and the like.

According to this aspect of the invention, methods of treating orpreventing a cancer in a human or veterinary animal suffering from orpredisposed to a cancer, comprise administering the compositionsdescribed herein, particularly the CMPs and CMPs and/or conjugates, intothe organ lumen, or into the cranium or into or on the brain, of a humanor veterinary animal, at a site proximal to the location of the canceror tumor. Without wishing to be bound by theory, the inventors surmisethat in areas of cancer there is sufficient disruption of type Icollagen, or upregulation of type I collagen in the case of braincancer, such that the CMP will target the site of the cancerspecifically and intercalate into the collagen structure, therebydelivering the CMP and/or therapeutic compound to the site where it mustact to treat, prevent or ameliorate the cancer. Particularly preferredconjugates or compositions for use in this aspect of the inventioninclude those wherein the therapeutic compound is a biologic therapeuticcompound, particularly one or more monoclonal antibodies or fragmentsthereof or one or more therapeutic fusion proteins, particularlyrecombinant fusion proteins, including those described herein.Additional preferred compositions comprise such compositions thatfurther comprise at least one growth factor, at least one antibiotic, atleast one antifungal compound or at least one antiviral compound.Suitable growth factors, antibiotics, antifungal compounds and antiviralcompounds include those described herein and others that are well-knownin the dermatological and other relevant arts. According to this aspectof the invention, the conjugates or compositions are suitably applied toor into the organ lumen, or the cranium or brain, in a dosage sufficientto treat, prevent or ameliorate the cancer, and the progression,remission or stasis of the cancer in the human or veterinary animal isthen monitored over time for improvement in the cancer disease state(e.g., shrinkage of the tumor or at least non-progression or remissionof the cancer). If necessary, the conjugate or composition of theinvention is then periodically readministered into the organ lumen, orinto the cranium or into or on the brain, according to dosing andtreatment schedules and protocols described herein and others that willbe familiar to the ordinarily skilled artisan, until the cancer iscured, prevented or ameliorated, or goes into permanent remission. Insuch embodiments, the conjugates or compositions of the invention aresuitably administered to or into the organ lumen or the brainparenterally or via direct application to the tumor site or, in the caseof excision or resection of the tumor, via direct application to thetumor bed or the wound remaining following excision or resection of thetumor. Parenteral administration of the conjugates or compositions ofthe invention can be accomplished via a route selected from the groupconsisting of subcutaneous injection, intravenous infusion,intraarterial infusion, transdermal diffusion, implantation of a drugeluting wafer or film, sublingually, orally, via aerosol inhalation,intravaginally, rectally, or intracranially. In certain such embodimentsthe conjugate or composition can be administered parenterally to thehuman or veterinary animal in the form of a mesh, film, wafer, sphere,nanoparticle, gel or patch that is implanted into the human orveterinary animal at or proximal to the site of the cancer. In othersuch embodiments, particularly those in which the cancer is anintraluminal cancer, the conjugates or compositions of the invention canbe administered to the lumen of the cancerous organ in the human orveterinary animal using a medical instrument suitable for such purpose,such as an endoscope, a bronchoscope (for example, via bronchial lavagefor treating, preventing or diagnosing a cancer of the pulmonary tractsuch as bronchial cancer or lung cancer), a proctoscope, a colonoscope,a cystoscope (e.g., into the bladder or upper urinary tract viacystoscopic irrigation), a gastroscope and a laparoscope, or othersuitable surgical/medical instruments capable of delivering a dose of amedicament such as the conjugates and compositions of the invention tothe human or veterinary animal at the site of the cancer. In certainsuch embodiments, the conjugate or composition can be administeredfollowing surgical excision or resection of a solid tumor, or removal oraspiration of a tumor ascites using, e.g., a trochar introduced into theabdomen for removal of abdominal ascites fluid. In such embodiments, theconjugate or composition of the invention (along with, optionally, oneor more additional therapeutic agents) can be introduced directly intothe surgical excision or into the ascites area, for example through anyof the instruments or devices described above.

In other embodiments, administration of the conjugates or compositionsto or into the organ lumen or the brain can be accomplished by anywell-known means, including in the form of a solution, an ointment, asalve, a patch, a cream, a topical solution and a drug eluting wafer.For example, the conjugates or compositions can be applied to orintroduced into the lumen of the organ or into or on the brain in theform of one or more drops of solution or a suspension that contains thecomposition or conjugates; via injection; in the form of a coating on asolid material that is implanted into the organ lumen or the brain; inthe form of a mesh or patch; by attaching the conjugate or compositionto, or enclosing it within, one or more nanoparticles that are thendelivered into the organ lumen or the brain. Other suitable methods ofapplying the conjugates or compositions to or into the organ lumen orthe brain to accomplish the therapeutic and diagnostic methods of theinvention will be readily apparent to the ordinarily skilled artisan.

Gastrointestinal diseases or disorders that can be treated, prevented,ameliorated or diagnosed using the compositions and methods of theinvention include but are not limited to irritable bowel syndrome,Crohn's Disease, an ulcer, ulcerative colitis, esophagitis, Barrett'sesophagitis, gastritis and proctitis.

According to this aspect of the invention, methods of treating orpreventing a gastrointestinal disease or disorder in a human orveterinary animal suffering from or predisposed to a gastrointestinaldisease or disorder comprise administering the compositions describedherein, particularly the CMPs and CMP-TC conjugates and compositionscomprising such CMPs and/or conjugates, into the gastrointestinal tractof a human or veterinary animal, at a site proximal to the location of alesion associated with or causing the gastrointestinal disease ordisorder. Without wishing to be bound by theory, the inventors surmisethat in areas of certain gastrointestinal diseases and disorders thereis sufficient disruption of type I collagen such that the CMP willtarget the site of the gastrointestinal disease or disorder specificallyand intercalate into the collagen structure, thereby delivering the CMPand/or therapeutic compound to the site where it must act to treat,prevent or ameliorate the gastrointestinal disease or disorder.Particularly preferred conjugates or compositions for use in this aspectof the invention include those wherein the therapeutic compound is abiologic therapeutic compound, particularly one or more monoclonalantibodies or fragments thereof or one or more therapeutic fusionproteins, particularly recombinant fusion proteins, including thosedescribed herein. According to this aspect of the invention, theconjugates or compositions are suitably applied to or into thegastrointestinal tract in a dosage sufficient to treat, prevent orameliorate the gastrointestinal disease or disorder, and theprogression, remission or stasis of the gastrointestinal disease ordisorder in the human or veterinary animal is then monitored over timefor improvement in the disease or disorder state. If necessary, theconjugate or composition of the invention is then periodicallyreadministered into the gastrointestinal tract according to dosing andtreatment schedules and protocols described herein and others that willbe familiar to the ordinarily skilled artisan, until thegastrointestinal disease or disorder is cured, prevented or ameliorated.In such embodiments, the conjugates or compositions of the invention aresuitably administered to or into the gastrointestinal tract parenterallyor topically. Parenteral administration is accomplished by any art-knownroute of administration of a therapy to the gastrointestinal tract, forexample via a route selected from the group consisting of subcutaneousinjection, intravenous infusion, intraarterial infusion, transdermaldiffusion, implantation of a drug eluting wafer, sublingually, orally orrectally. In such methods, the composition is suitably administeredparenterally to the human or veterinary animal in the form of a pill,capsule, solution, suspension or powder that is ingested by the human orveterinary animal, or in the form of a mesh or patch that is implantedwithin the gastrointestinal tract at or proximal to the site of thedisease or disorder. In other such embodiments, particularly those inwhich the disease or disorder is intraluminal in the gastrointestinaltract, the conjugates or compositions of the invention can beadministered to the lumen of the gastrointestinal organ in the human orveterinary animal using a medical instrument suitable for such purpose,such as a proctoscope, a colonoscope, a cystoscope (e.g., into thebladder or upper urinary tract cystoscopically), a gastroscope and alaparoscope, or other suitable surgical/medical instruments capable ofdelivering a dose of a medicament such as the conjugates andcompositions of the invention to the human or veterinary animal at thesite of the gastrointestinal disease or disorder.

In other embodiments, administration of the conjugates or compositionsto or into the gastrointestinal tract can be accomplished by anywell-known means, including in the form of a solution, an ointment, asalve, a patch, a cream, a topical solution and a drug eluting wafer.For example, the conjugates or compositions can be applied to orintroduced into the gastrointestinal tract in the form of one or moredrops of solution or a suspension that contains the composition orconjugates; via injection; in the form of a coating on a solid materialthat is implanted into the gastrointestinal tract; in the form of a meshor patch; by attaching the conjugate or composition to, or enclosing itwithin, one or more nanoparticles that are then delivered into thegastrointestinal tract. Other suitable methods of applying theconjugates or compositions to or into the gastrointestinal tract toaccomplish the therapeutic and diagnostic methods of the invention willbe readily apparent to the ordinarily skilled artisan.

Genitourinary diseases or disorders that can be treated, prevented,ameliorated or diagnosed using the compositions and methods of theinvention include but are not limited to female urinary incontinence,cystitis, interstitial cystitis, irritable bladder syndrome, ureteritisand vaginitis.

According to this aspect of the invention, methods of treating orpreventing a genitourinary disease or disorder in a human or veterinaryanimal suffering from or predisposed to a genitourinary disease ordisorder comprise administering the compositions described herein,particularly the CMPs and CMP-TC conjugates and compositions comprisingsuch CMPs and/or conjugates, into the genitourinary tract of a human orveterinary animal, at a site proximal to the location of a lesionassociated with or causing the genitourinary tract disease or disorder.Without wishing to be bound by theory, the inventors surmise that inareas of certain genitourinary diseases and disorders there issufficient disruption of type I collagen such that the CMP will targetthe site of the genitourinary disease or disorder specifically andintercalate into the collagen structure, thereby delivering the CMPand/or therapeutic compound to the site where it must act to treat,prevent or ameliorate the genitourinary disease or disorder. Accordingto this aspect of the invention, the conjugates or compositions aresuitably applied to or into the genitourinary tract in a dosagesufficient to treat, prevent or ameliorate the genitourinary disease ordisorder, and the progression, remission or stasis of the genitourinarydisease or disorder in the human or veterinary animal is then monitoredover time for improvement in the disease or disorder state. Ifnecessary, the conjugate or composition of the invention is thenperiodically readministered into the genitourinary tract according todosing and treatment schedules and protocols described herein and othersthat will be familiar to the ordinarily skilled artisan, until thegenitourinary disease or disorder is cured, prevented or ameliorated. Insuch embodiments, the conjugates or compositions of the invention aresuitably administered to or into the genitourinary tract parenterally ortopically. Parenteral administration is accomplished by any art-knownroute of administration of a therapy to the gastrointestinal tract, forexample via a route selected from the group consisting of subcutaneousinjection, intravenous infusion, intraarterial infusion, transdermaldiffusion, implantation of a drug eluting wafer, sublingually, orally,vaginally or rectally. In such methods, the composition is suitablyadministered parenterally to the human or veterinary animal in the formof a pill, capsule, solution, suspension or powder that is ingested bythe human or veterinary animal, or in the form of a mesh or patch thatis implanted within the genitourinary tract at or proximal to the siteof the disease or disorder. In other such embodiments, particularlythose in which the disease or disorder is intraluminal in thegastrointestinal tract, the conjugates or compositions of the inventioncan be administered to the lumen of the genitourinary organ in the humanor veterinary animal using a medical instrument suitable for suchpurpose, such as an endoscope, a vaginoscope, and a laparoscope, orother suitable surgical/medical instruments capable of delivering a doseof a medicament such as the conjugates and compositions of the inventionto the human or veterinary animal at the site of the genitourinarydisease or disorder.

In other embodiments, administration of the conjugates or compositionsto or into the genitourinary tract can be accomplished by any well-knownmeans, including in the form of a solution, an ointment, a salve, apatch, a wafer, a film, a gel, spheres, nanoparticles, a cream, atopical solution and a drug eluting wafer. For example, the conjugatesor compositions can be applied to or introduced into the genitourinarytract in the form of one or more drops of solution or a suspension thatcontains the composition or conjugates; via injection; in the form of acoating on a solid material that is implanted into the genitourinarytract; in the form of a mesh or patch; by attaching the conjugate orcomposition to, or enclosing it within, one or more nanoparticles thatare then delivered into the genitourinary tract. Other suitable methodsof applying the conjugates or compositions to or into the genitourinarytract to accomplish the therapeutic and diagnostic methods of theinvention will be readily apparent to the ordinarily skilled artisan.

Fibrotic diseases or disorders that can be treated, prevented,ameliorated or diagnosed using the compositions and methods of theinvention include but are not limited to pulmonary fibrosis, livercirrhosis, myocardial fibrosis, surgical scarring, systemic sclerosis,scleroderma, keloid formation, proliferative vitreo retinopathy, and thelike.

According to this aspect of the invention, methods of treating orpreventing a fibrotic disease or disorder in a human or veterinaryanimal suffering from or predisposed to a bone disease or disordercomprise administering the compositions described herein, particularlythe CMPs and CMP-TC conjugates and compositions comprising such CMPsand/or conjugates, into or near one or more tissues, organs or organsystems of a human or veterinary animal, at a site proximal to thelocation of a fibrotic lesion associated with or causing the fibroticdisease or disorder. Without wishing to be bound by theory, theinventors surmise that in areas of certain fibrotic diseases anddisorders there is sufficient disruption of type I collagen such thatthe CMP will target the site of the fibrotic disease or disorderspecifically and intercalate into the collagen structure, therebydelivering the therapeutic compound to the site where it must act totreat, prevent or ameliorate the fibrotic disease or disorder. Accordingto this aspect of the invention, the conjugates or compositions aresuitably applied to, near or into the tissue, organ or organ system in adosage sufficient to treat, prevent or ameliorate the fibrotic diseaseor disorder, and the progression, remission or stasis of the fibroticdisease or disorder in the human or veterinary animal is then monitoredover time for improvement in the disease or disorder state. Ifnecessary, the conjugate or composition of the invention is thenperiodically readministered into, near or onto one or more tissues,organs or organ systems according to dosing and treatment schedules andprotocols described herein and that will be familiar to the ordinarilyskilled artisan, until the fibrotic disease or disorder is cured,prevented or ameliorated. In such embodiments, the conjugates orcompositions of the invention are suitably administered to, near, on orinto the tissues, organs or organ systems parenterally or topically.Parenteral administration is accomplished by any art-known route ofadministration of a therapy to the tissues, organ or organ systems, forexample via a route selected from the group consisting of subcutaneousinjection, intravenous infusion, intraarterial infusion, endoscopicapplication, transdermal diffusion, implantation of a drug elutingwafer, film, gel or putty, sublingually, orally or rectally. In suchmethods, the composition is suitably administered parenterally to thehuman or veterinary animal in the form of a pill, capsule, solution,suspension or powder that is ingested by the human or veterinary animal,or in the form of a mesh, film, wafer, gel, sphere, nanoparticle, puttyor patch that is implanted near, on or into the fibrotic tissue, organor organ system at or proximal to the site of the disease or disorder.

In other embodiments, administration of the conjugates or compositionsto, near or into the tissues, organs or organ systems can beaccomplished by any well-known means, including in the form of asolution, an ointment, a salve, a patch, a film, a gel, spheres,nanoparticles, putty, a cream, a topical solution and a drug elutingwafer. For example, the conjugates or compositions can be applied to ornear, or introduced into, the tissues, organs or organ systems in theform of one or more drops of solution or a suspension that contains thecomposition or conjugates; via injection; in the form of a coating on asolid material that is implanted into, near or onto the tissues, organsor organ systems; in the form of a mesh or patch; by attaching theconjugate or composition to, or enclosing it within, one or morenanoparticles that are then delivered into, near or on the tissues,organs or organ systems. Other suitable methods of applying theconjugates or compositions to, on, near or into the tissues, organs ororgan systems to accomplish the therapeutic and diagnostic methods ofthe invention will be readily apparent to the ordinarily skilledartisan.

Cardiovascular diseases or disorders that can be treated, prevented,ameliorated or diagnosed using the compositions and methods of theinvention include but are not limited to myocardial infarction, cardiacinsufficiency, cardiac valve disorders, atherosclerosis,cardiomyophathy, arrhythmias, congenital heart disease, coronary arterydisease, pericardial disease, vascular occlusive disease (e.g.,affecting the carotid artery, the aorta, the renal artery, the femoralartery, the pulmonary artery, and other large vessels and small vesselswhich may be arteries, arterioles, veins, venules and the like), Marfansyndrome, and the like.

According to this aspect of the invention, methods of treating orpreventing a cardiovascular disease or disorder in a human or veterinaryanimal suffering from or predisposed to a cardiovascular disease ordisorder comprise administering the compositions described herein,particularly the CMPs and/or CMP-TC conjugates and compositionscomprising such CMPs and/or conjugates, into the vascular system of ahuman or veterinary animal suffering from or predisposed to such adisease or disorder. Without wishing to be bound by theory, theinventors surmise that in areas of certain cardiovascular diseases anddisorders there is sufficient disruption of type I collagen such thatthe CMP introduced into the vascular system of the subject will targetthe site of the cardiovascular disease or disorder specifically andintercalate into the collagen structure, thereby delivering the CMPand/or therapeutic compound to the site where it must act to treat,prevent or ameliorate the cardiovascular disease or disorder. Accordingto this aspect of the invention, the conjugates or compositions aresuitably applied to or into the vascular system in a dosage sufficientto treat, prevent or ameliorate the cardiovascular disease or disorder,and the progression, remission or stasis of the cardiovascular diseaseor disorder in the human or veterinary animal is then monitored overtime for improvement in the disease or disorder state. If necessary, theconjugate or composition of the invention is then periodicallyreadministered into the vascular system according to dosing andtreatment schedules and protocols described herein and others that willbe familiar to the ordinarily skilled artisan, until the cardiovasculardisease or disorder is cured, prevented or ameliorated. In suchembodiments, the conjugates or compositions of the invention aresuitably administered to or into the heart, pericardium, vessel or otherrelevant component of the vascular system parenterally or topically.Parenteral administration is accomplished by any art-known route ofadministration of a therapy to the vascular system, for example via aroute selected from the group consisting of subcutaneous injection,intravenous infusion, intraarterial infusion, transdermal diffusion, viacatheterization, embolization, implantation of a drug eluting wafer orfilm, sublingually, orally, rectally. In such methods, the compositionis suitably administered parenterally to the human or veterinary animalin the form of a pill, capsule, solution, suspension or powder that isingested by the human or veterinary animal, or in the form of a mesh,wafer, film, gel, putty, sphere, nanoparticle or patch that is implantedwithin the heart, pericardium, vessel or other relevant component of thevascular system at or proximal to the site involved in thecardiovascular disease or disorder.

In other embodiments, administration of the conjugates or compositionsto or into the vascular system can be accomplished by any well-knownmeans, including in the form of a solution, an ointment, a salve, apatch, a film, a gel, spheres, nanoparticles, a cream, a topicalsolution and a drug eluting wafer. For example, the conjugates orcompositions can be applied to or introduced into the heart,pericardium, vessel or other relevant component of the vascular systemin the form of one or more drops of solution or a suspension thatcontains the composition or conjugates; via injection; in the form of acoating on a solid material that is implanted into the heart,pericardium, vessel or other relevant component of the vascular system;in the form of a mesh or patch; by attaching the conjugate orcomposition to, or enclosing it within, one or more nanoparticles thatare then delivered into the heart, pericardium, vessel or other relevantcomponent of the vascular system. Other suitable methods of applying theconjugates or compositions to or into the vascular system to accomplishthe therapeutic and diagnostic methods of the invention will be readilyapparent to the ordinarily skilled artisan.

Bone diseases or disorders that can be treated, prevented, amelioratedor diagnosed using the compositions and methods of the invention includebut are not limited to osteoporosis, bone fracture, osteomyelitis,osteogenesis imperfecta, Paget disease of bone, osteonecrosis, rickets,osteomalacia, acromegaly and the like.

According to this aspect of the invention, methods of treating orpreventing a bone disease or disorder in a human or veterinary animalsuffering from or predisposed to a bone disease or disorder compriseadministering the compositions described herein, particularly the CMPsand CMP-TC conjugates and compositions comprising such CMPs and/orconjugates, into or near one or more bones of a human or veterinaryanimal, at a site proximal to the location of a lesion associated withor causing the bone disease or disorder. Without wishing to be bound bytheory, the inventors surmise that in areas of certain bone diseases anddisorders there is sufficient disruption of type I collagen such thatthe CMP will target the site of the bone disease or disorderspecifically and intercalate into the collagen structure, therebydelivering the therapeutic compound to the site where it must act totreat, prevent or ameliorate the bone disease or disorder. According tothis aspect of the invention, the conjugates or compositions aresuitably applied to, near or into the bone in a dosage sufficient totreat, prevent or ameliorate the bone disease or disorder, and theprogression, remission or stasis of the bone disease or disorder in thehuman or veterinary animal is then monitored over time for improvementin the disease or disorder state. If necessary, the conjugate orcomposition of the invention is then periodically readministered into,near or onto one or more bones according to dosing and treatmentschedules and protocols described herein and others that will befamiliar to the ordinarily skilled artisan, until the bone disease ordisorder is cured, prevented or ameliorated. In such embodiments, theconjugates or compositions of the invention are suitably administeredto, near, on or into the bones parenterally or topically. Parenteraladministration is accomplished by any art-known route of administrationof a therapy to the bones, for example via a route selected from thegroup consisting of subcutaneous injection, intravenous infusion,intraarterial infusion, endoscopic application, transdermal diffusion,implantation of a drug eluting wafer, film, gel or putty, sublingually,orally or rectally. In such methods, the composition is suitablyadministered parenterally to the human or veterinary animal in the formof a pill, capsule, solution, suspension or powder that is ingested bythe human or veterinary animal, or in the form of a mesh, film, wafer,gel, sphere, nanoparticle, putty or patch that is implanted near, on orinto the bone at or proximal to the site of the disease or disorder.

In other embodiments, administration of the conjugates or compositionsto, near or into the bones can be accomplished by any well-known means,including in the form of a solution, an ointment, a salve, a patch, afilm, a gel, spheres, nanoparticles, putty, a cream, a topical solutionand a drug eluting wafer. For example, the conjugates or compositionscan be applied to or near, or introduced into, the bones in the form ofone or more drops of solution or a suspension that contains thecomposition or conjugates; via injection; in the form of a coating on asolid material that is implanted into, near or onto the bones; in theform of a mesh or patch; by attaching the conjugate or composition to,or enclosing it within, one or more nanoparticles that are thendelivered into, near or on the bones. Other suitable methods of applyingthe conjugates or compositions to, on, near or into the bones toaccomplish the therapeutic and diagnostic methods of the invention willbe readily apparent to the ordinarily skilled artisan.

Rheumatic diseases or disorders that can be treated, prevented,ameliorated or diagnosed using the compositions and methods of theinvention include but are not limited to arthritis (particularlyrheumatoid arthritis, osteoarthritis and psoriatic arthritis), bursitis,crepitus, spondylosis, scleroderma, polymyalgia rheumatica andanarthritic syndrome.

According to this aspect of the invention, methods of treating orpreventing a rheumatic disease or disorder in a human or veterinaryanimal suffering from or predisposed to a rheumatic disease or disordercomprise administering the compositions described herein, particularlythe CMPs or CMP-TC conjugates and compositions comprising such CMPsand/or conjugates, to the human or veterinary animal at a site proximalto the location of a lesion associated with or causing the rheumaticdisease or disorder. Without wishing to be bound by theory, theinventors surmise that in areas of certain rheumatic diseases anddisorders there is sufficient disruption of type I collagen such thatthe CMP will target the site of the rheumatic disease or disorderspecifically and intercalate into the collagen structure, therebydelivering the therapeutic compound to the site where it must act totreat, prevent or ameliorate the rheumatic disease or disorder.According to this aspect of the invention, the conjugates orcompositions are suitably applied to or into the human or veterinaryanimal in a dosage sufficient to treat, prevent or ameliorate therheumatic disease or disorder, and the progression, remission or stasisof the rheumatic disease or disorder in the human or veterinary animalis then monitored over time for improvement in the disease or disorderstate. If necessary, the conjugate or composition of the invention isthen periodically readministered to the human or veterinary animalaccording to dosing and treatment schedules and protocols describedherein and others that will be familiar to the ordinarily skilledartisan, until the rheumatic disease or disorder is cured, prevented orameliorated. In such embodiments, the conjugates or compositions of theinvention are suitably administered to or into the human or veterinaryanimal parenterally or topically. Parenteral administration isaccomplished by any art-known route of administration of a therapydesigned to treat, prevent or ameliorate a rheumatic disease ordisorder, for example via a route selected from the group consisting ofsubcutaneous injection, intravenous infusion, intraarterial infusion,transdermal diffusion, implantation of a drug eluting wafer,sublingually, orally, vaginally or rectally. In such methods, thecomposition is suitably administered parenterally to the human orveterinary animal in the form of a pill, capsule, solution, suspensionor powder that is ingested by the human or veterinary animal, or in theform of a mesh or patch that is implanted within the human or veterinaryanimal at or proximal to the site of the disease or disorder. In othersuch embodiments, particularly those in which the rheumatic disease ordisorder is located in or near a bone, tendon, cartilage, ligament,bursa, joint or associated structure, the compositions or conjugates ofthe invention are suitably administered to the human or veterinaryanimal using a medical instrument suitable for such purpose, such as anlaparoscope, or other suitable surgical/medical instruments capable ofdelivering a dose of a medicament such as the conjugates andcompositions of the invention to the human or veterinary animal at thesite of the genitourinary disease or disorder.

In other embodiments, administration of the conjugates or compositionsto or into the human or veterinary animal can be accomplished by anywell-known means, including in the form of a solution, an ointment, asalve, a patch, a cream, a topical solution and a drug eluting wafer.For example, the conjugates or compositions can be applied to orintroduced into the human or veterinary animal in the form of one ormore drops of solution or a suspension that contains the composition orconjugates; via injection; in the form of a coating on a solid materialthat is implanted into the human or veterinary animal; in the form of amesh or patch; by attaching the conjugate or composition to, orenclosing it within, one or more nanoparticles that are then deliveredinto the human or veterinary animal. Other suitable methods of applyingthe conjugates or compositions to or into the human or veterinary animalto accomplish the therapeutic and diagnostic methods of the inventionwill be readily apparent to the ordinarily skilled artisan.

In related embodiments, the invention provides devices, particularlymedical devices, suitable for treating or preventing a disease, disorderor medical condition in a human or veterinary animal suffering from orpredisposed to said disease, disorder or medical condition. Such devicessuitably will comprise at least one of the compositions of the presentinvention, in the form of a coating on the device or a composition thatis embedded within the device such that it is released from or elutesfrom the device once implanted within the body of the human orveterinary animal. Suitable such devices include, but are not limitedto, artificial joints, stents, catheters, sutures, bone screws, boneplates, prosthetics (e.g., artificial limbs, body structures, organs,etc.), absorbable or non-absorbable meshes, absorbable or non-absorbablepatches, drug-releasing wafers, brain neurostimulators (e.g., deep brainneurostimulators), gastric stimulators, cochlear implants, cardiacdefibrillators, cardiac pacemakers, insulin pumps, internal infusionpumps, and the like. Suitable other devices useful in accordance withthis aspect of the invention will be readily apparent to the ordinarilyskilled artisan.

The devices provided by this aspect of the invention are useful fortreating, preventing, ameliorating or diagnosing diseases, disorders andmedical conditions in humans or veterinary animals suffering from orpredisposed to such diseases, disorders or medical conditions. Inmethods according to this aspect, one or more medical devices of theinvention is implanted into the human or veterinary animal, and medicalcondition of the human or veterinary animal is monitored until thedisease, disorder or medical condition is cured, ameliorated orprevented in the human or veterinary animal. Suitable diseases,disorders and medical conditions that may be cured, treated, amelioratedor prevented using the devices and methods of the invention includecancers (such as those described elsewhere herein), and diseases ordisorders affecting an organ system of the human or veterinary animalincluding the integumentary system (particularly diseases or disordersof the skin such as those described in detail herein), the muscularsystem, the skeletal system (particularly diseases or disorder of thebones, joints, cartilage, tendons or ligaments such as those describedin detail herein), the nervous system (particularly those of the brainor the eye (including but not limited to glaucoma, cataracts, vitreousadhesions or floaters, macular degeneration, dry eye syndrome, cornealkeratitis, non-infectious corneal ulceration, non-infectious cornealmelting, infectious corneal ulceration, infectious corneal melting,conjunctivitis, Stevens-Johnson Syndrome, scleritis, episcleritis,ectasia, keratoconus, corneal laceration, corneal erosion, cornealabrasion, and a post-operative affliction of the eye resulting from eyesurgery such as a post-operative cataract surgery state requiringmedication or a post-operative glaucoma surgery state requiringmedication)), the circulatory system, the lymphatic system, therespiratory system (including those diseases or disorders affecting theepiglottis, the trachea, a bronchus, a bronchiole or a lung in the humanor veterinary animal, particularly those diseases and disordersdescribed in detail herein), the endocrine system, the urinary/excretorysystem (including those diseases or disorders affecting the kidney, theureter, the urinary bladder, the upper urinary tract (i.e., the renalpelvis), the ureter or the urethra of the human or veterinary animal,particularly those diseases and disorders described in detail herein),the reproductive system (including diseases and disorders affecting thetesticle, the prostate, the penis, the vagina, the cervix, the uterus, afallopian tube or an ovary in said human or veterinary animal,particularly those diseases and disorders described in detail herein)and the digestive system (including those diseases or disordersaffecting the esophagus, stomach, small intestine, colon or rectum insaid human or veterinary animal, particularly those diseases anddisorders described in detail herein). Suitable methods for implantingone or more of the devices provided by this aspect of the invention intoa human or veterinary animal, to accomplish the treatment, prevention,amelioration or diagnosis of a disease, disorder or medical or physicalcondition in the human or veterinary animal will be familiar to theperson of ordinary skill in the relevant medical and surgical arts.

Concentrations of the CMPs, or of the CMP-TC conjugates, useful intreating, preventing, ameliorating or diagnosing one or more diseases ordisorders according to the methods of the present invention will bereadily apparent to the artisan ordinarily skilled in the pharmaceuticaland medical arts. For unconjugated CMPs, suitable amounts orconcentrations of CMPs to be administered to a subject, particularly ahuman or veterinary animal, suitable amounts or concentrations of CMPsper kilogram (kg) of body mass are from about 1 mg/kg to about 10 mg/kg,about 1 mg/kg to about 5 mg/kg, and about 1 mg/kg, about 2 mg/kg, about3 mg/kg, about 4 mg/kg, or about 5 mg/kg. For conjugated CMP-TCs, thesame amounts or concentrations of CMPs per kg of body mass are suitablyadministered to the subject, and the amount of active pharmaceuticalingredient or biologic is calculated during the conjugation process todeliver therapeutically effective amounts of the desired activepharmaceutical ingredient or biologic, depending upon the disease ordisorder that is to be treated, prevented, ameliorated or diagnosed inthe human or veterinary animal. Suitable amounts or concentrations ofactive pharmaceutical ingredients or biologics to be used according tothis aspect of the invention will be familiar to the ordinarily skilledartisan, and can be readily determined from information contained hereinand other information that is available in the relevant arts.

It will be readily apparent to one of ordinary skill in the relevantarts that other suitable modifications and adaptations to the methodsand applications described herein may be made without departing from thescope of the invention or any embodiment thereof. Having now describedthe present invention in detail, the same will be more clearlyunderstood by reference to the following examples, which are includedherewith for purposes of illustration only and are not intended to belimiting of the invention.

EXAMPLES Example 1: Effect of CMPs and CMP-TC Conjugates on In VivoHealing of Mouse Corneal Epithelium

To examine the possible therapeutic effects of CMPs and CMP-TCconjugates of the invention, studies were designed to test certain CMPsand CMP-TC conjugates in an in vivo setting—the healing of the cornealepithelium in wounded mouse eyes. Female mice (8-week-old C57BL/6; sevenmice per sample tested) were anesthetized, and corneas of the mouse eyeswere wounded with a 1.5 mm superficial epithelial wound of sufficientdepth to expose the anterior stroma thereby damaging and exposing thecollagen matrix. Wounds were created via trephine, followed by anAlgerbrush scouring technique (see Carlson, E., et al., “Impact ofHyaluronic Acid-Containing Artificial Tear Products onReepithelialization in an In Vivo Corneal Wound Model,” J. OcularPharmacol. Ther., published online Feb. 2, 2018, accessed atdoi.org/10.1089/jop.2017.0080). Following wounding, corneas were treatedwith 25 nM (about 3 mg/kg) CMPs or CMP-TC conjugates, in aqueous PBS.Negative control mice were treated with vehicle only (PBS), and positivecontrol mice were treated with 100 ng/mL epidermal growth factor (EGF).Wound size at various time points over 48 hours was examined byfluorescein staining (see Carlson et al., id.), and documented viafluorescent photomicrography, and quantified using Image J software (seeRush, J. S. et al., Investig. Ophthalmol. Visual Sci. 57(14):5864-5871(2016); Rush, J. S. et al., Investig. Ophthalmol. Visual Sci.55(8):4691-4699 (2014)). Results are depicted in the FIGURE.

The FIGURE shows that the CMPs and CMP-TC conjugates of the inventionsignificantly accelerated the reepithelialization and healing of thesubepithelial stroma in the cornea of mouse eyes, vs. both EGF andvehicle. The left-hand column shows the size of the wound (visualized asthe circle of fluorescein fluorescence in each photomicrograph)immediately after induction of the wound, while the right-hand columnshows the size of the wound 16 hours post-wounding and post-treatmentwith various test substances. PBS: negative control; EGF: positivecontrol. “Cmpd 3”: a (Pro-Pro-Gly)′ CMP of the invention (SEQ ID NO:1);“Cmpd 10”: a (Hyp-Pro-Gly)₇ CMP—Substance P (SubP) conjugate of theinvention (SEQ ID NO:390). The results demonstrate that both Cmpd 3 andCmpd 10 demonstrated significant acceleration of wound healing in mousecornea and corneal stroma (indicated by a reduction in the diameter anddiminution in intensity of the fluorescence) within 16 hourspost-treatment, compared to both PBS and EGF controls which showed alower level of healing. These results support the use of the CMPs andCMP-TC conjugates of the present invention in promoting corneal woundhealing and stromal collagen repair in wounded mouse eye, a model of avariety of human and veterinary animal ocular conditions including dryeye and corneal laceration or ulceration of a variety of etiologies.

The present invention has been described above with the aid offunctional building blocks illustrating the implementation of specifiedfunctions and relationships thereof. The boundaries of these functionalbuilding blocks have been arbitrarily defined herein for the convenienceof the description. Alternate boundaries can be defined so long as thespecified functions and relationships thereof are appropriatelyperformed.

The foregoing description of the specific embodiments will so fullyreveal the general nature of the invention that others can, by applyingknowledge within the skill of the art, readily modify and/or adapt forvarious applications such specific embodiments, without undueexperimentation, without departing from the general concept of thepresent invention. Hence, in addition to those specifically describedherein, other suitable embodiments of the invention will be readilyapparent to one of ordinary skill in the art based upon the foregoingdescription and examples, and upon knowledge generally available in therelevant arts. Therefore, such adaptations and modifications areintended to be within the meaning and range of equivalents of thedisclosed embodiments, based on the teaching and guidance presentedherein. It is to be understood that the phraseology or terminologyherein is for the purpose of description and not of limitation, suchthat the terminology or phraseology of the present specification is tobe interpreted by the skilled artisan in light of the teachings andguidance.

The breadth and scope of the present invention should not be limited byany of the above-described exemplary embodiments but should be definedonly in accordance with the following claims and their equivalents.

All references cited herein, including U.S. patents and published patentapplications, international patents and patent applications, and journalreferences or other publicly available documents, are incorporatedherein by reference in their entireties to the same extent as if eachreference had been specifically cited for the portion or portions ofsuch reference applicable to the section of this application to which itis relevant.

What is claimed is:
 1. A composition for treating an ocular disease,disorder or wound selected from the group consisting of glaucoma, dryeye syndrome, conjunctivitis, corneal keratitis, corneal laceration,corneal erosion, corneal abrasion, cataracts, vitreous adhesions orfloaters, non-infectious corneal ulceration, non-infectious cornealmelting, infectious corneal ulceration, infectious corneal melting,Stevens-Johnson Syndrome, scleritis, episcleritis, ectasia, keratoconus,and post-operative afflictions of the eye resulting from eye surgery, ina human or veterinary animal suffering said disease or disorder, saidcomposition comprising (a) at least one collagen mimetic peptide (CMP)comprising the amino acid sequence of SEQ ID NO: 6, and (b) one or morepharmaceutically suitable carriers, said composition formulated todeliver the at least one CMP to a cornea of an eye of the human orveterinary animal to enable the CMP to intercalate into disrupted type Icollagen in the eye.
 2. The composition of claim 1, wherein said oculardisease, disorder or wound is selected from the group consisting ofkeratoconus, cataracts and post-operative afflictions of the eyeresulting from eye surgery.
 3. The composition of claim 1, wherein saidocular disease, disorder or wound is keratoconus.
 4. The composition ofclaim 1, wherein said ocular disease, disorder or wound is cataracts. 5.The composition of claim 1, wherein said ocular disease, disorder orwound is post-operative afflictions of the eye resulting from eyesurgery.
 6. The composition of claim 1, wherein said composition isformulated to deliver at least one CMP to the eye conjunctively.
 7. Thecomposition of claim 1, wherein said composition is formulated todeliver at least one CMP to the eye subconjunctivally.
 8. Thecomposition of claim 7, wherein said composition is formulated todeliver at least one CMP into the subconjunctival fornix.
 9. Thecomposition of claim 1, wherein said composition is formulated as one ormore drops of solution or a suspension that contains the composition.10. The composition of claim 1, wherein said composition is formulatedfor delivery via injection.
 11. The composition of claim 1, wherein saidcomposition is formulated in the form of a coating on a solid materialfor implanting into an eye structure.
 12. The composition of claim 1,wherein said composition is formulated in the form of a wafer, film,gel, mesh or patch.
 13. The composition of claim 1, wherein saidcomposition is attached to one or more spheres or nanoparticles fordelivery to or into an eye structure.
 14. The composition of claim 1,wherein said collagen mimetic peptide is attached to at least onetherapeutic compound (TC) to form a CMP-TC conjugate.
 15. Thecomposition of claim 14, wherein said at least one therapeutic compoundcomprises at least one reactive hydroxyl group capable of beingcross-linked to said collagen mimetic peptide.
 16. The composition ofclaim 15, wherein said at least one therapeutic compound is directlyattached to said collagen mimetic peptide via an amino group on saidcollagen mimetic peptide linked to a hydroxyl group on said therapeuticcompound.
 17. The composition of claim 14, wherein said at least onetherapeutic compound is selected from the group consisting of asteroidal anti-inflammatory drug, a nonsteroidal anti-inflammatory drug,a topical anesthetic, a vitamin or a derivative or precursor thereof,therapeutic enzyme or a therapeutic fragment thereof, an antibiotic, atherapeutic monoclonal antibody or a therapeutic fragment thereof, atherapeutic fusion protein, a prostaglandin analogue, a growth factor, aneuropeptide, an α-adrenergic antagonist, a β-adrenergic antagonist, acell surface receptor antagonist, a carbonic anhydrase inhibitor, andpharmaceutically acceptable salts, esters and derivatives thereof. 18.The composition of claim 17, wherein said prostaglandin analogue isselected from the group consisting of latanoprost, travoprost,tafluprost, unoprostone, tatanoprostene bunod and bimatoprost, andpharmaceutically acceptable salts, esters and derivatives thereof. 19.The composition of claim 18, wherein said prostaglandin analogue islatanoprost.
 20. The composition of claim 14, wherein said collagenmimetic peptide is covalently attached directly to said at least onetherapeutic compound.
 21. The composition of claim 14, wherein saidcollagen mimetic peptide is indirectly attached to said at least onetherapeutic compound via use of an attachment means.
 22. The compositionof claim 21, wherein said attachment means comprises at least onepolymeric chain having a first end and a second end.
 23. The compositionof claim 22, wherein said polymeric chain is a linear polyethyleneglycolchain comprising at least four ethyleneglycol monomers.
 24. Thecomposition of claim 23, wherein said polymeric chain comprises fromtwenty to twenty-five ethyleneglycol monomers.
 25. The composition ofclaim 14, wherein said collagen mimetic peptide comprises at least onebiotin moiety and said therapeutic molecule comprises at least oneavidin or streptavidin moiety, and wherein said biotin moiety on saidcollagen mimetic peptide binds to said avidin or streptavidin moiety onsaid therapeutic compound, thereby attaching said collagen mimeticpeptide to said therapeutic compound.
 26. The composition of claim 14,wherein said collagen mimetic peptide comprises at least one avidin orstreptavidin moiety and said therapeutic molecule comprises at least onebiotin moiety, and wherein said avidin or streptavidin moiety on saidcollagen mimetic peptide binds to said biotin moiety on said therapeuticcompound, thereby attaching said collagen mimetic peptide to saidtherapeutic compound.